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Birgersson M, Holm M, Gallardo-Dodd CJ, Chen B, Stepanauskaitė L, Hases L, Kutter C, Archer A, Williams C. Intestinal estrogen receptor beta modulates the murine colon tumor immune microenvironment. Cancer Lett 2025; 622:217661. [PMID: 40120798 DOI: 10.1016/j.canlet.2025.217661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/07/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
Chronic inflammation contributes to the development of colorectal cancer, partly through its regulation of the microenvironment and antitumor immunity. Interestingly, women have a lower incidence of colorectal cancer, and estrogen treatment has been shown to reduce the occurrence of colorectal tumors. While intestinal estrogen receptor beta (ERβ, Esr2) can protect against colitis and colitis-induced cancer in mice, its role in shaping the tumor microenvironment remains unknown. In this study, we performed RNA sequencing to analyze the transcriptome of colonic epithelia and tumors from azoxymethane/dextran sulfate sodium-treated wild-type and intestinal ERβ knockout (ERβKOVil) mice and vehicle-treated controls. This revealed significant differences in gene expression and enriched biological processes influenced by sex and genotype, with immune-related responses being overrepresented. Deconvolution supported differential immune cell abundance and immunostaining showed that tumors from ERβKOVil mice displayed significantly increased macrophage infiltration, decreased T cell infiltration, and impaired natural killer cell infiltration. Further, ERβ mRNA levels in clinical colorectal tumors correlated with immune signaling profiles and better survival. Our findings indicate that intestinal ERβ promotes an antitumor microenvironment and could potentially affect the effectiveness of immunotherapy. These insights highlight the importance of ERβ in modulating antitumor immunity and underscore its therapeutic potential in colorectal cancer.
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Affiliation(s)
- Madeleine Birgersson
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Matilda Holm
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Carlos J Gallardo-Dodd
- Department of Microbiology, Tumor and Cell Biology, SciLifeLab, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Baizhen Chen
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden
| | - Lina Stepanauskaitė
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Linnea Hases
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Claudia Kutter
- Department of Microbiology, Tumor and Cell Biology, SciLifeLab, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Amena Archer
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Cecilia Williams
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, 171 21 Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, 141 83, Huddinge, Sweden.
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Zheng L, Li Y, Güngör C, Ge H. Gut microbiota influences colorectal cancer through immune cell interactions: a Mendelian randomization study. Discov Oncol 2025; 16:747. [PMID: 40358736 DOI: 10.1007/s12672-025-02486-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the most prevalent malignant tumor of the digestive system globally, posing a significant threat to human health and quality of life. Recent studies have established associations between gut microbiota and immune cells with CRC; however, the mechanisms by which gut microbiota influence the development and progression of CRC through immune mediators remain poorly understood. METHODS We conducted a two-sample, bidirectional Mendelian randomization analysis. We utilized 731 immune cell types and 473 gut microbial species along with colorectal cancer statistics from published summary statistics from genome-wide association studies (GWAS).The analysis employed several methodologies, including inverse variance-weighted (IVW) analysis, MR-Egger regression, the weighted median method, and both weighted and simple model approaches.Sensitivity analyses were performed to confirm the reliability of the Mendelian randomization results, and reverse Mendelian randomization was used to assess the overall impact of CRC on gut microbiota and immune cells. RESULTS Our findings suggest a causal relationship involving nine immunophenotypes and five specific gut microbial taxa with CRC. Notably, the gut microbes Alloprevotella and Holdemania, along with immune cell types CD3 on CD28- CD8br and CD4 + T cells, demonstrated significant causal associations with CRC. Mediation analysis revealed that the association between Alloprevotella and CRC was mediated by CD4 + T cells, with a mediation effect of 6.48%. Additionally, Holdemania was found to mediate its association with CRC through CD3 on CD28- CD8br, exhibiting a mediation effect of 9.29%. Reverse Mendelian randomization did not indicate any causal effect of CRC on specific immune cells or gut microbiota. Two-sided sensitivity analyses revealed no evidence of heterogeneity or horizontal pleiotropy in our findings. CONCLUSIONS This comprehensive Mendelian randomization study enhances our understanding of the mechanisms by which gut microbiota affects CRC through immune cell interactions. Further investigations are warranted to unravel the underlying mechanisms linking gut microbiota, immune cells, and colorectal cancer.
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Affiliation(s)
- Linyi Zheng
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Yuqiang Li
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Cenap Güngör
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Heming Ge
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, 410013, China.
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Hatim MS, Al-Saffar AZ, Al-Aadhami MAWS. 5-Bromouracil-gracillin (5BrU-G) complex: an APOBEC3-activated therapeutic strategy exploiting cancer-specific enzymatic activity for selective cytotoxicity. Med Oncol 2025; 42:203. [PMID: 40335833 DOI: 10.1007/s12032-025-02745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/25/2025] [Indexed: 05/09/2025]
Abstract
Recent cancer treatment development has focused on smart drugs, primarily using nanomaterials as carriers. However, concerns about nanomaterial fate and body clearance have led to exploring alternative approaches. This study presents a novel targeted smart drug that uses normal lymphocytic cells as carriers and exploits cancer microenvironment characteristics for drug release, avoiding systemic damage. The research investigated a complex combining gracillin (natural carrier) and the chemotherapeutic agent 5-bromouracil (5-BrU). Molecular docking showed the 5BrU-G complex had superior binding affinity (- 7.96 kcal mol-1) to glycosylated adhesion domain of human T lymphocyte glycoprotein CD2 (1CDB) cell surface receptors in silico. The complex was successfully synthesized through double replacement, precipitation, and neutralization reactions, confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cytotoxic and genotoxic studies revealed the selectivity of 5BrU-G against cancer cells (MDA-MB-231 and Caco-2) while saving normal cells (MCF-10A and CCD 841 CoN). Unlike 5-BrU alone, which showed significant genotoxicity in normal cells, the 5BrU-G complex demonstrated minimal toxic effects. The selective targeting mechanism of 5BrU-G relies on APOBEC3 enzyme activity, which is elevated in cancer cells but is absent in normal cells. This was confirmed when APOBEC3 inhibition prevented the complex's cancer-killing activity. This novel approach offers promising alternatives for improving cancer therapy efficacy while reducing side effects.
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Affiliation(s)
- Mays S Hatim
- Department of Molecular and Medical Biotechnology, College of Biotechnology, Al-Nahrain University, Baghdad, Iraq
| | - Ali Z Al-Saffar
- Department of Molecular and Medical Biotechnology, College of Biotechnology, Al-Nahrain University, Baghdad, Iraq.
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Ghorbaninezhad F, Nour MA, Farzam OR, Saeedi H, Vanan AG, Bakhshivand M, Jafarlou M, Hatami-Sadr A, Baradaran B. The tumor microenvironment and dendritic cells: Developers of pioneering strategies in colorectal cancer immunotherapy? Biochim Biophys Acta Rev Cancer 2025; 1880:189281. [PMID: 39929377 DOI: 10.1016/j.bbcan.2025.189281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 01/25/2025] [Accepted: 02/04/2025] [Indexed: 02/13/2025]
Abstract
Colorectal cancer (CRC) is the world's third most frequent cancer, and both its incidence and fatality rates are rising. Despite various therapeutic approaches, neither its mortality rate nor its recurrence frequency has decreased significantly. Additionally, conventional treatment approaches, such as chemotherapy and radiotherapy, have several side effects and risks for patients with CRC. Accordingly, the need for alternative and effective treatments for CRC patients is critical. Immunotherapy that utilizes dendritic cells (DCs) harnesses the patient's immune system to combat cancer cells effectively. DCs are the most potent antigen-presenting cells (APCs), which play a vital role in generating anti-cancer T cell responses. A significant barrier to the immune system's ability to eliminate CRC is the establishment of a potent immunosuppressive tumor milieu by malignant cells. Since DCs are frequently defective in this milieu, the tumor setting significantly reduces the effectiveness of DC-based therapy. Determining central mechanisms contributing to tumor growth by unraveling and comprehending the interaction between CRC tumor milieu and DCs may lead to new therapeutic approaches. This study aims to review DC biology and discuss its role in T-cell-mediated anti-tumor immunity, as well as to highlight the immunosuppressive effects of the CRC tumor milieu on the function of DCs. We will also highlight the tumor microenvironment (TME)-related factors that interfere with DC function as a possible therapeutic target to enhance DC-based cell therapy efficacy.
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Affiliation(s)
- Farid Ghorbaninezhad
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mina Afrashteh Nour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Omid Rahbar Farzam
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Saeedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Ghorbani Vanan
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mohammad Bakhshivand
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Jafarlou
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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5
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Liu X, Liu D, Tan C, Wang J. Systemic immune profiling analysis identifying M2-TAM related genes predicted colon cancer prognosis and chemotherapy responses. Medicine (Baltimore) 2024; 103:e40979. [PMID: 39969348 PMCID: PMC11688056 DOI: 10.1097/md.0000000000040979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/27/2024] [Indexed: 02/20/2025] Open
Abstract
Colon cancer (COAD) poses great challenges to clinical treatment due to its heterogeneity and complex immune microenvironment. M2-like macrophages significantly influence COAD's onset, progression, and treatment. Yet, existing M2-like macrophage markers are limited in prognostic efficacy, prompting the exploration of new M2 signatures. Extensive data analysis aimed to unveil prognosis-associated M2-derived signatures. Bulk transcriptome, single-cell RNA sequencing, and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus databases for patients with COAD were amassed. Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts identified immune cell infiltration, and the Kaplan-Meier test identified crucial immune populations associated with prognosis. Genetic signatures linked to M2 tumor-associated macrophage were crafted utilizing weighted gene coexpression network analysis, least absolute shrinkage and selection operator, and Cox regression. The M2 tumor-associated macrophage gene signature was validated in GSE17536. The expression profile of the M2 gene signature was investigated in single-cell RNA sequencing dataset GSE166555. Systemic immune profile identified that M2-like macrophage has the most significant prognostic significance in The Cancer Genome Atlas-COAD. The core genes related to M2 macrophage infiltration were extracted by weighted gene coexpression network analysis. Least absolute shrinkage and selection operator-stepwise COX regression-derived M2-derived signatures (snail family zinc finger 1, gastrin-releasing peptide, gamma-aminobutyric acid type A receptor delta subunit, cluster of differentiation 1B, poly(A)-binding protein cytoplasmic 2, manic fringe, and death-associated protein kinase 1) as a risk model, which was confirmed as independent prognosis factors, validated by external dataset. This M2-based prognostic model reflected M2 macrophage infiltration. Mendelian randomization established cytotoxic T lymphocyte associate protein-4 and cluster of differentiation 274 immune checkpoints' causality with COAD. In conclusion, our study developed novel markers for discriminating M2-like macrophages and predicting the prognosis of patients with COAD, offering fresh perspectives for clinical interventions.
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Affiliation(s)
- Xiaopei Liu
- School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Dan Liu
- Department of Anorectal, Xi’an Hospital of Traditional Chinese Medicine, Xianyang, China
| | - Cong’e Tan
- School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jiehong Wang
- Department of Gastroenterology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
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Matsubara Y, Ota Y, Denda T, Tanaka Y, Isobe M, Kato S, Konuma T, Takahashi S, Hirata Y, Ikematsu H, Baba K, Boku N. Both Th1 and Th2 CD4 + T-Cell Lineage Infiltrations Decrease in Post-hematopoietic Stem Cell Transplantation Colon Adenoma. J Gastrointest Cancer 2024; 55:1551-1558. [PMID: 39158838 DOI: 10.1007/s12029-024-01097-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2024] [Indexed: 08/20/2024]
Abstract
PURPOSE As long-term survival improves after allogeneic hematopoietic stem cell transplantation (HSCT), the risk for secondary solid cancers, including colon cancer, also increases. However, the pathogenesis of secondary solid cancers in post-HSCT patients remains unclear. This study aimed to investigate the involvement of local immunity in colon carcinogenesis in post-HSCT patients by assessing the infiltrating T cells in colon adenomas as premalignant lesions of colon cancer in adenoma-carcinoma sequence. METHODS Colon adenoma samples obtained from 19 post-HSCT patients and 57 non-HSCT participants were analyzed via immunohistochemistry. Double staining of CD4/T-bet, CD4/GATA3, and CD4/FoxP3 was performed for evaluation of helper T-cell lineages (Th1, Th2, and regulatory T cells, respectively) and CD8 staining for CD8+ T cells. RESULTS There were no significant between-group differences in the number of infiltrating CD4+ T cells and CD8+ T cells in adenomas. However, the number of both CD4+/T-bet+ and CD4+/GATA3+ T cells was significantly lower in the post-HSCT adenomas than in the non-HSCT adenomas (P = 0.0171 and 0.0009, respectively), whereas no significant differences were found in the number of CD4+/FoxP3+ cells. CONCLUSION Although the number of infiltrating CD4+ and CD8+ T cells, and even Treg cell counts, is sufficiently recovered post-HSCT, CD4+ T-cell dysfunction due to suppressed activation and differentiation in colon adenomas might be involved in colon carcinogenesis in post-HSCT patients. Elucidating the pathogenesis will contribute to the development of effective screening and prevention programs for secondary colon cancer in post-HSCT patients.
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Affiliation(s)
- Yasuo Matsubara
- Department of Oncology and General Medicine, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan.
- Department of Gastroenterology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan.
| | - Yasunori Ota
- Department of Diagnostic Pathology, Institute of Medical Science, IMSUT Hospital, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Tamami Denda
- Department of Diagnostic Pathology, Institute of Medical Science, IMSUT Hospital, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Yukihisa Tanaka
- Department of Diagnostic Pathology, Institute of Medical Science, IMSUT Hospital, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Yoshihiro Hirata
- Department of Gastroenterology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Hiroaki Ikematsu
- Department of Gastroenterology, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Keisuke Baba
- Department of Oncology and General Medicine, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Narikazu Boku
- Department of Oncology and General Medicine, Institute of Medical Science, IMSUT Hospital, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
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Tangella N, Cess CG, Ildefonso GV, Finley SD. Integrating mechanism-based T cell phenotypes into a model of tumor-immune cell interactions. APL Bioeng 2024; 8:036111. [PMID: 39175956 PMCID: PMC11341129 DOI: 10.1063/5.0205996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 08/21/2024] [Accepted: 07/25/2024] [Indexed: 08/24/2024] Open
Abstract
Interactions between cancer cells and immune cells in the tumor microenvironment influence tumor growth and can contribute to the response to cancer immunotherapies. It is difficult to gain mechanistic insights into the effects of cell-cell interactions in tumors using a purely experimental approach. However, computational modeling enables quantitative investigation of the tumor microenvironment, and agent-based modeling, in particular, provides relevant biological insights into the spatial and temporal evolution of tumors. Here, we develop a novel agent-based model (ABM) to predict the consequences of intercellular interactions. Furthermore, we leverage our prior work that predicts the transitions of CD8+ T cells from a naïve state to a terminally differentiated state using Boolean modeling. Given the details incorporated to predict T cell state, we apply the integrated Boolean-ABM framework to study how the properties of CD8+ T cells influence the composition and spatial organization of tumors and the efficacy of an immune checkpoint blockade. Overall, we present a mechanistic understanding of tumor evolution that can be leveraged to study targeted immunotherapeutic strategies.
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Affiliation(s)
- Neel Tangella
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, California 90089, USA
| | - Colin G. Cess
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA
| | - Geena V. Ildefonso
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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Kang Q, He L, Zhang Y, Zhong Z, Tan W. Immune-inflammatory modulation by natural products derived from edible and medicinal herbs used in Chinese classical prescriptions. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155684. [PMID: 38788391 DOI: 10.1016/j.phymed.2024.155684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/29/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use. PURPOSE Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs. STUDY DESIGN In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation. METHODS Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively. RESULTS More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized. CONCLUSION Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.
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Affiliation(s)
- Qianming Kang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Luying He
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Yang Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
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Siguenza N, Brevi A, Zhang JT, Pabani A, Bhushan A, Das M, Ding Y, Hasty J, Ghosh P, Zarrinpar A. Engineered bacterial therapeutics for detecting and treating CRC. Trends Cancer 2024; 10:588-597. [PMID: 38693003 PMCID: PMC11392429 DOI: 10.1016/j.trecan.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 05/03/2024]
Abstract
Despite an overall decrease in occurrence, colorectal cancer (CRC) remains the third most common cause of cancer deaths in the USA. Detection of CRC is difficult in high-risk groups, including those with genetic predispositions, with disease traits, or from certain demographics. There is emerging interest in using engineered bacteria to identify early CRC development, monitor changes in the adenoma and CRC microenvironment, and prevent cancer progression. Novel genetic circuits for cancer therapeutics or functions to enhance existing treatment modalities have been tested and verified in vitro and in vivo. Inclusion of biocontainment measures would prepare strains to meet therapeutic standards. Thus, engineered bacteria present an opportunity for detection and treatment of CRC lesions in a highly sensitive and specific manner.
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Affiliation(s)
- Nicole Siguenza
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Arianna Brevi
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Joanna T Zhang
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Arman Pabani
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA
| | - Abhinav Bhushan
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA
| | - Moumita Das
- School of Physics and Astronomy, Rochester Institute of Technology, Rochester, NY, USA
| | - Yousong Ding
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL, USA
| | - Jeff Hasty
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA; Synthetic Biology Institute, University of California, San Diego, La Jolla, CA, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
| | - Pradipta Ghosh
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Amir Zarrinpar
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA; Synthetic Biology Institute, University of California, San Diego, La Jolla, CA, USA; Jennifer Moreno Department of Veterans Affairs, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
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Rodríguez-Santiago Y, Garay-Canales CA, Nava-Castro KE, Morales-Montor J. Sexual dimorphism in colorectal cancer: molecular mechanisms and treatment strategies. Biol Sex Differ 2024; 15:48. [PMID: 38867310 PMCID: PMC11170921 DOI: 10.1186/s13293-024-00623-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 05/26/2024] [Indexed: 06/14/2024] Open
Abstract
INTRODUCTION Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development. MAIN BODY The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies. CONCLUSIONS Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies.
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Affiliation(s)
- Yair Rodríguez-Santiago
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacán, Mexico City, 04510, México
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Edificio D, 1er piso, Circuito de Posgrados, Ciudad Universitaria, Ciudad de México, 04510, México
| | - Claudia Angelica Garay-Canales
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacán, Mexico City, 04510, México
| | - Karen Elizabeth Nava-Castro
- Grupo de Biología y Química Atmosféricas, Instituto de Ciencias de la Atmósfera y Cambio Climático, Universidad Nacional Autónoma de México, Ciudad Universitaria, CDMX, 04510, México
| | - Jorge Morales-Montor
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacán, Mexico City, 04510, México.
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12
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Choi MJ, Kang SJ, Lee YK, Choi KC, Lee DH, Jeong HY, Kim MW, Kim KS, Park YS. Novel Lipid Nanocomplex Co-Carrying Bcl2 siRNA and Quantum Dots for EGF Receptor-Targeted Anti-Cancer Theranosis. Int J Mol Sci 2024; 25:6246. [PMID: 38892434 PMCID: PMC11172456 DOI: 10.3390/ijms25116246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Many different types of nanoparticles have been suggested for tumor-targeted theranosis. However, most systems were prepared through a series of complicated processes and could not even overcome the blood-immune barriers. For the accurate diagnosis and effective treatment of cancers, herein we suggested the lipid micellar structure capturing quantum dot (QD) for cancer theranosis. The QD/lipid micelles (QDMs) were prepared using a simple self-assembly procedure and then conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for tumor targeting. As a therapeutic agent, Bcl2 siRNA-cholesterol conjugates were loaded on the surface of QDMs. The EGFR-directed QDMs containing Bcl2 siRNA, so-called immuno-QDM/siBcl2 (iQDM/siBcl2), exhibited the more effective delivery of QDs and siBcl2 to target human colorectal cancer cells in cultures as well as in mouse xenografts. The effective in vivo targeting of iQDM/siBcl2 resulted in a more enhanced therapeutic efficacy of siBcl2 to the target cancer in mice. Based on the results, anti-EGFR QDM capturing therapeutic siRNA could be suggested as an alternative modality for tumor-targeted theranosis.
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Affiliation(s)
- Moon Jung Choi
- Department of Medicine, Brown University, Providence, RI 02903, USA;
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
| | - Seong Jae Kang
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
| | - Yeon Kyung Lee
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
| | - Kang Chan Choi
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
| | - Do Hyun Lee
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
| | - Hwa Yeon Jeong
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Min Woo Kim
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Keun Sik Kim
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Republic of Korea;
| | - Yong Serk Park
- Department of Biomedical Laboratory Science, Yonsei University, Wonju 26496, Republic of Korea; (S.J.K.); (Y.K.L.); (K.C.C.); (D.H.L.); (H.Y.J.); (M.W.K.)
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13
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Gherman A, Bolundut D, Ecea R, Balacescu L, Curcean S, Dina C, Balacescu O, Cainap C. Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:397. [PMID: 38541123 PMCID: PMC10972200 DOI: 10.3390/medicina60030397] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/10/2024] [Accepted: 02/18/2024] [Indexed: 11/12/2024]
Abstract
Currently, only a limited set of molecular traits are utilized to direct treatment for metastatic CRC (mCRC). The molecular classification of CRC depicts tumor heterogeneity based on gene expression patterns and aids in comprehending the biological characteristics of tumor formation, growth and prognosis. Additionally, it assists physicians in tailoring the therapeutic approach. Microsatellite instability (MSI-H)/deficient mismatch repair proteins (MMRd) status has become a ubiquitous biomarker in solid tumors, caused by mutations or methylation of genes and, in turn, the accumulation of mutations and antigens that subsequently induce an immune response. Immune checkpoint inhibitors (ICI) have recently received approval for the treatment of mCRC with MSI-H/MMRd status. However, certain individuals experience either initial or acquired resistance. The tumor-programmed cell death ligand 1 (PD-L1) has been linked to the ability of CRC to evade the immune system and promote its growth. Through comprehensive research conducted via the PUBMED database, the objectives of this paper were to review the molecular characteristics linked to tumor response in metastatic CRC in light of improved patients' outcomes following ICI therapies as seen in clinical trials and to identify particular microRNAs that can modulate the expression of specific oncoproteins, such as PD-L1, and disrupt the mechanisms that allow the immune system to be evaded.
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Affiliation(s)
- Alexandra Gherman
- 10th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (A.G.); (C.C.)
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
| | - Dinu Bolundut
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
| | - Radu Ecea
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
| | - Loredana Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania;
| | - Sebastian Curcean
- 10th Department of Radiation Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania;
- Department of Radiation Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Constantin Dina
- Department of Anatomy, Faculty of Medicine, Ovidius University, 124 Mamaia Boulevard, 900527 Constanta, Romania
| | - Ovidiu Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania;
| | - Calin Cainap
- 10th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (A.G.); (C.C.)
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
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Jepsen DNM, Høeg H, Bzorek M, Orhan A, Eriksen JO, Gögenur I, Reiss B, Fiehn AMK. Digitally assessed lymphocyte infiltration in rectal cancer biopsies is associated with pathological response to neoadjuvant therapy. Hum Pathol 2024; 144:61-70. [PMID: 38157991 DOI: 10.1016/j.humpath.2023.12.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/19/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024]
Abstract
A frequently used treatment strategy in locally advanced rectal cancer (RC) is neoadjuvant therapy followed by surgery. Patients treated with neoadjuvant therapy achieve varying pathological response, and currently, predicting the degree of response is challenging. This study examined the association between digitally assessed histopathological features in the diagnostic biopsies and pathological response to neoadjuvant therapy, aiming to find potential predictive biomarkers. 50 patients with RC treated with neoadjuvant chemotherapy and/or radiotherapy followed by surgery were included. Deep learning-based digital algorithms were used to assess the epithelium tumor area percentage (ETP) based on H&E-stained slides, and to quantify the density of CD3+ and CD8+ lymphocytes, as well as the CD8+/CD3+ lymphocyte percentage, based on immunohistochemically stained slides, from the diagnostic tumor biopsies. Pathological response was assessed according to the Mandard method. A good pathological response was defined as tumor regression grade (TRG) 1-2, and a complete pathological response was defined as Mandard TRG 1. Associations between the ETP and lymphocyte densities in the diagnostic biopsies and the pathological response were examined. The density of CD8+ lymphocytes, and the CD8+/CD3+ lymphocyte percentage, were associated with both good and complete response to neoadjuvant therapy, while the density of CD3+ lymphocytes was associated with complete response. The ETP did not correlate with response to neoadjuvant therapy. It is well-known that infiltration of lymphocytes in colorectal cancer is a prognostic biomarker. However, assessment of CD8+ and CD3+ lymphocytes in the diagnostic tumor biopsies of patients with RC may also be useful in predicting response to neoadjuvant therapy.
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Affiliation(s)
- Dea Natalie Munch Jepsen
- Department of Pathology, Zealand University Hospital, Denmark; Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark.
| | | | - Michael Bzorek
- Department of Pathology, Zealand University Hospital, Denmark.
| | - Adile Orhan
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark; Department of Clinical Oncology, Zealand University Hospital, Denmark.
| | | | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark.
| | | | - Anne-Marie Kanstrup Fiehn
- Department of Pathology, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark.
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15
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Li X, Wu D, Li Q, Gu J, Gao W, Zhu X, Yin W, Zhu R, Zhu L, Jiao N. Host-microbiota interactions contributing to the heterogeneous tumor microenvironment in colorectal cancer. Physiol Genomics 2024; 56:221-234. [PMID: 38073489 DOI: 10.1152/physiolgenomics.00103.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/15/2023] [Accepted: 12/01/2023] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer (CRC) exhibits pronounced heterogeneity and is categorized into four widely accepted consensus molecular subtypes (CMSs) with unique tumor microenvironments (TMEs). However, the intricate landscape of the microbiota and host-microbiota interactions within these TMEs remains elusive. Using RNA-sequencing data from The Cancer Genome Atlas, we analyzed the host transcriptomes and intratumoral microbiome profiles of CRC samples. Distinct host genes and microbial genera were identified among the CMSs. Immune microenvironments were evaluated using CIBERSORTx and ESTIMATE, and microbial coabundance patterns were assessed with FastSpar. Through LASSO penalized regression, we explored host-microbiota associations for each CMS. Our analysis revealed distinct host gene signatures within the CMSs, which encompassed ferroptosis-related genes and specific immune microenvironments. Moreover, we identified 293, 153, 66, and 109 intratumoral microbial genera with differential abundance, and host-microbiota associations contributed to distinct TMEs, characterized by 829, 1,270, 634, and 1,882 robust gene-microbe associations for each CMS in CMS1-CMS4, respectively. CMS1 featured inflammation-related HSF1 activation and gene interactions within the endothelin pathway and Flammeovirga. Integrin-related genes displayed positive correlations with Sutterella in CMS2, whereas CMS3 spotlighted microbial associations with biosynthetic and metabolic pathways. In CMS4, genes involved in collagen biosynthesis showed positive associations with Sutterella, contributing to disruptions in homeostasis. Notably, immune-rich subtypes exhibited pronounced ferroptosis dysregulation, potentially linked to tissue microbial colonization. This comprehensive investigation delineates the diverse landscapes of the TME within each CMS, incorporating host genes, intratumoral microbiota, and their complex interactions. These findings shed light on previously uncharted mechanisms underpinning CRC heterogeneity and suggest potential therapeutic targets.NEW & NOTEWORTHY This study determined the following: 1) providing a comprehensive landscape of consensus molecular subtype (CMS)-specific tumor microenvironments (TMEs); 2) constructing CMS-specific networks, including host genes, intratumoral microbiota, and enriched pathways, analyzing their associations to uncover unique patterns that demonstrate the intricate interplay within the TME; and 3) revealing a connection between immune-rich subtypes and ferroptosis activation, suggesting a potential regulatory role of the microbiota in ferroptosis dysregulation of the colorectal cancer TME.
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Affiliation(s)
- Xiaoyi Li
- Department of Nephrology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Dingfeng Wu
- Department of Nephrology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Qiuyu Li
- Department of Nephrology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jinglan Gu
- Department of Nephrology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Wenxing Gao
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China
| | - Xinyue Zhu
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China
| | - Wenjing Yin
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China
| | - Ruixin Zhu
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China
| | - Lixin Zhu
- Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Na Jiao
- Department of Nephrology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
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16
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Sunakawa Y, Kuboki Y, Watanabe J, Terazawa T, Kawakami H, Yokota M, Nakamura M, Kotaka M, Sugimoto N, Ojima H, Oki E, Kajiwara T, Yamamoto Y, Tsuji Y, Denda T, Tamura T, Ishihara S, Taniguchi H, Nakajima TE, Morita S, Shirao K, Takenaka N, Ozawa D, Yoshino T. Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer. Target Oncol 2024; 19:59-69. [PMID: 38194163 PMCID: PMC10830797 DOI: 10.1007/s11523-023-01027-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER jRCTs031180122.
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Affiliation(s)
- Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.
| | - Yasutoshi Kuboki
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Jun Watanabe
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Tetsuji Terazawa
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Japan
| | - Mitsuru Yokota
- Department of General Surgery, Kurashiki Central Hospital, Kurashiki, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan
| | | | - Naotoshi Sugimoto
- Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Hitoshi Ojima
- Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ota, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Takeshi Kajiwara
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Yoshiyuki Yamamoto
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, Tonan Hospital, Sapporo, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Takao Tamura
- Department of Medical Oncology, Kindai University Nara Hospital, Ikoma, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takako Eguchi Nakajima
- Department of Early Clinical Development, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Naruhito Takenaka
- Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan
| | - Daisuke Ozawa
- Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Rossetti M, Stanca S, Del Frate R, Bartoli F, Marciano A, Esposito E, Fantoni A, Erba AP, Lippolis PV, Faviana P. Tumor Progression from a Fibroblast Activation Protein Perspective: Novel Diagnostic and Therapeutic Scenarios for Colorectal Cancer. Diagnostics (Basel) 2023; 13:3199. [PMID: 37892020 PMCID: PMC10606275 DOI: 10.3390/diagnostics13203199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/09/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
In 2020, the Global Cancer Observatory estimated the incidence of colorectal cancer (CRC) at around 10.7% coupled with a mortality rate of 9.5%. The explanation for these values lies in the tumor microenvironment consisting of the extracellular matrix and cancer-associated fibroblasts (CAFs). Fibroblast activation protein (FAP) offers a promising target for cancer therapy since its functions contribute to tumor progression. Immunohistochemistry examination of FAP, fibronectin ED-B, and CXCR4 in primary tumors and their respective synchronous and/or metachronous metastases along with semiquantitative analysis have been carried out on histological samples of 50 patients diagnosed with metastatic CRC. The intensity of FAP, articulated by both "Intensity %" and "Intensity score", is lower in the first metastasis compared to the primary tumor with a statistically significant correlation. No significant correlations have been observed regarding fibronectin ED-B and CXCR4. Tumors that produce FAP have an ambivalent relationship with this protein. At first, they exploit FAP, but later they reduce its expressiveness. Although our study has not directly included FAP-Inhibitor (FAPI) PET/CT, the considerable expression of FAP reveals its potential as a diagnostic and therapeutic tool worthy of further investigation. This dynamic relationship between cancer and FAP has substantial diagnostic and therapeutic implications.
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Affiliation(s)
- Martina Rossetti
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy; (M.R.); (S.S.); (R.D.F.); (A.F.)
| | - Stefano Stanca
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy; (M.R.); (S.S.); (R.D.F.); (A.F.)
| | - Rossella Del Frate
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy; (M.R.); (S.S.); (R.D.F.); (A.F.)
| | - Francesco Bartoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (F.B.); (A.M.); (E.E.)
| | - Andrea Marciano
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (F.B.); (A.M.); (E.E.)
| | - Enrica Esposito
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (F.B.); (A.M.); (E.E.)
| | - Alessandra Fantoni
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy; (M.R.); (S.S.); (R.D.F.); (A.F.)
| | - Anna Paola Erba
- Department of Medicine and Surgery, University of Milan Bicocca and Nuclear Medicine Unit ASST Ospedale Papa Giovanni XXIII Bergamo, 24127 Bergamo, Italy;
| | | | - Pinuccia Faviana
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy; (M.R.); (S.S.); (R.D.F.); (A.F.)
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18
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Zhao Y, Guo M, Zhao F, Liu Q, Wang X. Colonic stem cells from normal tissues adjacent to tumor drive inflammation and fibrosis in colorectal cancer. Cell Commun Signal 2023; 21:186. [PMID: 37528407 PMCID: PMC10391886 DOI: 10.1186/s12964-023-01140-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 04/22/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND In colorectal cancer (CRC), the normal tissue adjacent to tumor (NAT) communicates actively with the tumor. Adult stem cells from the colon play a crucial role in the development of the colonic epithelium. In the tumor microenvironment, however, it is unclear what changes have occurred in colonic stem cells derived from NAT. METHODS Using an intestinal stem cell culture system, we cultured colonic cells from NAT and paired CRC tissue, as well as cells from healthy tissue (HLT). Clonogenicity and differentiation ability were used to compare the function of clones from NAT, HLT and CRC tissues. RNA high-throughput sequencing of these clones was used to identify the molecular characteristics of NAT-derived clones. Coculture of clones from HLT and CRC was used to assess molecular changes. RESULTS We found that the morphological characteristics, clonogenic ability, and differentiation ability of NAT-derived clones were consistent with those of HLT-derived clones. However, NAT-derived clones changed at the molecular level. A number of genes were specifically activated in NAT. NAT-derived clones enriched pathways related to inflammation and fibrosis, including epithelial mesenchymal transition (EMT) pathway and TGF-beta signaling pathway. Our results also confirmed that NAT-derived clones could recruit fibroblasts in mice. In addition, HLT-derived clones showed high expression of FOSB when cocultured with tumor cells. CONCLUSIONS Our results demonstrate that colonic stem cells from NAT in the tumor microenvironment undergo changes at the molecular level, and these molecular characteristics can be maintained in vitro, which can induce fibrosis and an inflammatory response. Video Abstract.
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Affiliation(s)
- Yuanyuan Zhao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Mengmeng Guo
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Fuqiang Zhao
- Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qian Liu
- Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xia Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
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19
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Chandrasekar SV, Singh A, Ranjan A. Overcoming Resistance to Immune Checkpoint Inhibitor Therapy Using Calreticulin-Inducing Nanoparticle. Pharmaceutics 2023; 15:1693. [PMID: 37376141 PMCID: PMC10302072 DOI: 10.3390/pharmaceutics15061693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/31/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Nanoparticles (NPs) have the ability to transform poorly immunogenic tumors into activated 'hot' targets. In this study, we investigated the potential of a liposome-based nanoparticle (CRT-NP) expressing calreticulin as an in-situ vaccine to restore sensitivity to anti-CTLA4 immune checkpoint inhibitor (ICI) in CT26 colon tumors. We found that a CRT-NP with a hydrodynamic diameter of approximately 300 nm and a zeta potential of approximately +20 mV induced immunogenic cell death (ICD) in CT-26 cells in a dose-dependent manner. In the mouse model of CT26 xenograft tumors, both CRT-NP and ICI monotherapy caused moderate reductions in tumor growth compared to the untreated control group. However, the combination therapy of CRT-NP and anti-CTLA4 ICI resulted in remarkable suppression of tumor growth rates (>70%) compared to untreated mice. This combination therapy also reshaped the tumor microenvironment (TME), achieving the increased infiltration of antigen-presenting cells (APCs) such as dendritic cells and M1 macrophages, as well as an abundance of T cells expressing granzyme B and a reduction in the population of CD4+ Foxp3 regulatory cells. Our findings indicate that CRT-NPs can effectively reverse immune resistance to anti-CTLA4 ICI therapy in mice, thereby improving the immunotherapeutic outcome in the mouse model.
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Affiliation(s)
| | | | - Ashish Ranjan
- Department of Physiological Sciences, College of Veterinary, Oklahoma State University, Stillwater, OK 74078, USA; (S.V.C.)
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20
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Kabiri F, Medlej A, Saleh AJ, Aghdami N, Khani M, Soltani BM. Downregulated miR-495-3p in colorectal cancer targets TGFβR1, TGFβR2, SMAD4 and BUB1 genes and induces cell cycle arrest. Cancer Treat Res Commun 2023; 35:100702. [PMID: 37044020 DOI: 10.1016/j.ctarc.2023.100702] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023]
Abstract
BACKGROUND Hsa-miR-495 (miR-495) has been extensively investigated in cancer initiation and progression. On the other hand, our bioinformatics analysis suggested that miR-495 exerts its effects through targeting of TGFβ signaling components. METHODS & RESULTS In order to investigate such an effect, miR-495 precursor was overexpressed in HEK293T, SW480, and HCT116 cells, which was followed by downregulation of TGFβR1, TGFβR2, SMAD4, and BUB1 putative target genes, detected by RT-qPCR. Also, luciferase assay supported the direct interaction of miR-495 with 3'UTR sequences of TGFβR1, TGFβR2, SMAD4, and BUB1 genes. Furthermore, a negative correlation of expression between miR-495-3p and some of these target genes was deduced in a set of colorectal and breast cancer cell lines. Then, flow cytometry analysis showed that the overexpression of miR-495 in HCT116 and HEK293T resulted in an arrest at the G1 phase. Consistently, western blotting analysis showed a significant reduction of the Cyclin D1 protein in the cells overexpressing miR-495, pointing to downregulation of the TGFβ signaling pathway and cell cycle arrest. Finally, microarray data analysis showed that miR-495-3p is significantly downregulated in colorectal tumors, compared to the normal pairs. CONCLUSIONS Overall, the results of the current study introduced miR-495-3p as a cell cycle progression suppressor, which may negatively regulate TGFβR1, TGFβR2, SMAD4, and BUB1 genes. This finding suggests miR-495-3p as a tumor suppressor candidate for further evaluation.
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Affiliation(s)
- Farnoush Kabiri
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University Tehran, Iran
| | | | - Ali Jason Saleh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University Tehran, Iran
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran
| | - Mona Khani
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University Tehran, Iran
| | - Bahram M Soltani
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University Tehran, Iran.
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21
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Ben Hamouda S, Essafi-Benkhadir K. Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24065600. [PMID: 36982677 PMCID: PMC10057671 DOI: 10.3390/ijms24065600] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
The study of the tumor microenvironment (TME) has become an important part of colorectal cancer (CRC) research. Indeed, it is now accepted that the invasive character of a primary CRC is determined not only by the genotype of the tumor cells, but also by their interactions with the extracellular environment, which thereby orchestrates the development of the tumor. In fact, the TME cells are a double-edged sword as they play both pro- and anti-tumor roles. The interaction of the tumor-infiltrating cells (TIC) with the cancer cells induces the polarization of the TIC, exhibiting an antagonist phenotype. This polarization is controlled by a plethora of interconnected pro- and anti-oncogenic signaling pathways. The complexity of this interaction and the dual function of these different actors contribute to the failure of CRC control. Thus, a better understanding of such mechanisms is of great interest and provides new opportunities for the development of personalized and efficient therapies for CRC. In this review, we summarize the signaling pathways linked to CRC and their implication in the development or inhibition of the tumor initiation and progression. In the second part, we enlist the major components of the TME and discuss the complexity of their cells functions.
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22
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Al Bitar S, El-Sabban M, Doughan S, Abou-Kheir W. Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond. World J Gastroenterol 2023; 29:1395-1426. [PMID: 36998426 PMCID: PMC10044855 DOI: 10.3748/wjg.v29.i9.1395] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/12/2022] [Accepted: 11/16/2022] [Indexed: 03/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide. Despite advances in therapeutic regimens, the number of patients presenting with metastatic CRC (mCRC) is increasing due to resistance to therapy, conferred by a small population of cancer cells, known as cancer stem cells. Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC. Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC, and these include vascular endothelial growth factor, epidermal growth factor receptor, human epidermal growth factor receptor-2, mitogen-activated extracellular signal-regulated kinase, in addition to immune checkpoints. Currently, there are several ongoing clinical trials of newly developed targeted agents, which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy. In this review, we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC. Furthermore, we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies, in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.
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Affiliation(s)
- Samar Al Bitar
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Marwan El-Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
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23
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Modulation of the Tumor Microenvironment by Microbiota-Derived Short-Chain Fatty Acids: Impact in Colorectal Cancer Therapy. Int J Mol Sci 2023; 24:ijms24065069. [PMID: 36982144 PMCID: PMC10048801 DOI: 10.3390/ijms24065069] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023] Open
Abstract
Finding new therapeutic approaches towards colorectal cancer (CRC) is of increased relevance, as CRC is one of the most common cancers worldwide. CRC standard therapy includes surgery, chemotherapy, and radiotherapy, which may be used alone or in combination. The reported side effects and acquired resistance associated with these strategies lead to an increasing need to search for new therapies with better efficacy and less toxicity. Several studies have demonstrated the antitumorigenic properties of microbiota-derived short-chain fatty acids (SCFAs). The tumor microenvironment is composed by non-cellular components, microbiota, and a great diversity of cells, such as immune cells. The influence of SCFAs on the different constituents of the tumor microenvironment is an important issue that should be taken into consideration, and to the best of our knowledge there is a lack of reviews on this subject. The tumor microenvironment is not only closely related to the growth and development of CRC but also affects the treatment and prognosis of the patients. Immunotherapy has emerged as a new hope, but, in CRC, it was found that only a small percentage of patients benefit from this treatment being closely dependent on the genetic background of the tumors. The aim of this review was to perform an up-to-date critical literature review on current knowledge regarding the effects of microbiota-derived SCFAs in the tumor microenvironment, particularly in the context of CRC and its impact in CRC therapeutic strategies. SCFAs, namely acetate, butyrate, and propionate, have the ability to modulate the tumor microenvironment in distinct ways. SCFAs promote immune cell differentiation, downregulate the expression of pro-inflammatory mediators, and restrict the tumor-induced angiogenesis. SCFAs also sustain the integrity of basement membranes and modulate the intestinal pH. CRC patients have lower concentrations of SCFAs than healthy individuals. Increasing the production of SCFAs through the manipulation of the gut microbiota could constitute an important therapeutic strategy towards CRC due to their antitumorigenic effect and ability of modulating tumor microenvironment.
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24
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The Colorectal Cancer Microbiota Alter Their Transcriptome To Adapt to the Acidity, Reactive Oxygen Species, and Metabolite Availability of Gut Microenvironments. mSphere 2023; 8:e0062722. [PMID: 36847536 PMCID: PMC10117117 DOI: 10.1128/msphere.00627-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
The gut microbiome is implicated in the pathology of colorectal cancer (CRC). However, the mechanisms by which the microbiota actively contribute to disease onset and progression remain elusive. In this pilot study, we sequenced fecal metatranscriptomes of 10 non-CRC and 10 CRC patient gut microbiomes and conducted differential gene expression analyses to assess any changed functionality in disease. We report that oxidative stress responses were the dominant activity across cohorts, an overlooked protective housekeeping role of the human gut microbiome. However, expression of hydrogen peroxide and nitric oxide-scavenging genes was diminished and augmented, respectively, positing that these regulated microbial responses have implications for CRC pathology. CRC microbes enhanced expression of genes for host colonization, biofilm formation, genetic exchange, virulence determinants, antibiotic, and acid resistances. Moreover, microbes promoted transcription of genes involved in metabolism of several beneficial metabolites, suggesting their contribution to patient metabolite deficiencies previously solely attributed to tumor cells. We showed in vitro that expression of genes involved in amino acid-dependent acid resistance mechanisms of meta-gut Escherichia coli responded differently to acid, salt, and oxidative pressures under aerobic conditions. These responses were mostly dictated by the host health status of origin of the microbiota, suggesting their exposure to fundamentally different gut conditions. These findings for the first time highlight mechanisms by which the gut microbiota can either protect against or drive colorectal cancer and provide insights into the cancerous gut environment that drives functional characteristics of the microbiome. IMPORTANCE The human gut microbiota has the genetic potential to drive colorectal cancer onset and progression; however, the expression of this genetic potential during the disease has not been investigated. We found that microbial expression of genes that detoxify DNA-damaging reactive oxygen species, which drive colorectal cancer, is compromised in cancer. We observed a greater activation of expression of genes involved in virulence, host colonization, exchange of genetic material, metabolite utilization, defense against antibiotics, and environmental pressures. Culturing gut Escherichia coli of cancerous and noncancerous metamicrobiota revealed different regulatory responses of amino acid-dependent acid resistance mechanisms in a health-dependent manner under environmental acid, oxidative, and osmotic pressures. Here, for the first time, we demonstrate that the activity of microbial genomes is regulated by the health status of the gut in vivo and in vitro and provides new insights for shifts in microbial gene expression in colorectal cancer.
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25
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Scheurlen KM, Snook DL, Alfieri T, Littlefield AB, George JB, Seraphine C, Cook CN, Rochet A, Gaskins JT, Galandiuk S. Obesity hormones and itaconate mediating inflammation in human colon cancer cells - Another lead to early-onset colon cancer? Heliyon 2023; 9:e13132. [PMID: 36825172 PMCID: PMC9941943 DOI: 10.1016/j.heliyon.2023.e13132] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
Background Chronic inflammation is a key feature of obesity and a hallmark of colon cancer (CC). The obesity-related hormones leptin and adiponectin alter inflammatory gene profiles in cancer, but their specific role in CC is unclear. We have previously studied the effects of leptin and the macrophage-specific mediator itaconate on M2-like macrophages. This current study evaluates their effects on CC cells. Methods HT-29 CC cells (derived from a young patient, stage III CC) were treated with either leptin, adiponectin, 4-octyl itaconate (OI) or dimethyl itaconate (DI). Gene expression after treatment was analyzed at four time points (3, 6, 18, and 24 h). Results CCL22 was upregulated after treatment with adiponectin (at 18 h [FC 16.3, p < 0.001]). IL-8 expression increased following both adiponectin (at 3 h [FC 68.1, p < 0.001]) and leptin treatments (at 6 h [FC 7.3, p < 0.001]), while OI induced downregulation of IL-8 (at 24 h [FC -5.0, p < 0.001]). CXCL10 was upregulated after adiponectin treatment (at 6 h [FC 3.0, p = 0.025]) and downregulated by both OI and DI at 24 h, respectively (OI [FC -10.0, p < 0.001]; DI [FC -10.0, p < 0.001]). IL-1β was upregulated after adiponectin treatment (at 3 h [FC 10.6, p < 0.001]) and downregulated by DI (at 24 h [FC -5.0, p < 0.001]). TNF-α expression was induced following adiponectin (at 6 h [FC 110.7, p < 0.001]), leptin (at 18 h [FC 5.8, p = 0.027]) and OI (at 3 h [FC 91.1, p = 0.001]). PPARγ was affected by both OI (at 3 h [FC 10.1, p = 0.031], at 24 h [FC -10.0, p = 0.031]) and DI (at 18 h [FC -1.7, p = 0.033]). Conclusions Obesity hormones directly affect inflammatory gene expression in HT29 CC cells, potentially enhancing cancer progression. Itaconate affects the prognostic marker PPARγ in HT29 CC cells. Leptin, adiponectin and itaconate may represent a link between obesity and CC.
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Affiliation(s)
- Katharina M. Scheurlen
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Dylan L. Snook
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Toriana Alfieri
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Andrew B. Littlefield
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Joan B. George
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Caden Seraphine
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Cheyenne N. Cook
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Andre Rochet
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Jeremy T. Gaskins
- Department of Bioinformatics & Biostatistics, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA,Corresponding author. @UofLDeptofSurg
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26
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Li DD, Tang YL, Wang X. Challenges and exploration for immunotherapies targeting cold colorectal cancer. World J Gastrointest Oncol 2023; 15:55-68. [PMID: 36684057 PMCID: PMC9850757 DOI: 10.4251/wjgo.v15.i1.55] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/28/2022] [Accepted: 12/07/2022] [Indexed: 01/10/2023] Open
Abstract
In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from “cold tumors” or “hot tumors”. At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a “hot tumor”, with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are “cold”. The greatest challenge today is how to improve the immunotherapy response of “cold tumor” patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of “cold tumors” to “hot tumors” and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.
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Affiliation(s)
- Dan-Dan Li
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yuan-Ling Tang
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Cai D, Wang W, Zhong ME, Fan D, Liu X, Li CH, Huang ZP, Zhu Q, Lv MY, Hu C, Duan X, Wu XJ, Gao F. An immune, stroma, and epithelial-mesenchymal transition-related signature for predicting recurrence and chemotherapy benefit in stage II-III colorectal cancer. Cancer Med 2023; 12:8924-8936. [PMID: 36629124 PMCID: PMC10134284 DOI: 10.1002/cam4.5534] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 10/27/2022] [Accepted: 12/02/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Debates exist on the treatment decision of the stage II/III colorectal cancer (CRC) due to the insufficiency of the current TNM stage-based risk stratification system. Epithelial-mesenchymal transition (EMT) and tumor microenvironment (TME) have both been linked to CRC progression in recent studies. We propose to improve the prognosis prediction of CRC by integrating TME and EMT. METHODS In total, 2382 CRC patients from seven datasets and one in-house cohort were collected, and 1640 stage II/III CRC patients with complete survival information and gene expression profiles were retained and divided into a training cohort and three independent validation cohorts. Integrated analysis of 398 immune, stroma, and epithelial-mesenchymal transition (ISE)-related genes identified an ISE signature independently associated with the recurrence of CRC. The underlying biological mechanism of the ISE signature and its influence on adjuvant chemotherapy was further explored. RESULTS We constructed a 26-gene signature which was significantly associated with poor outcome in Training cohort (p < 0.001, HR [95%CI] = 4.42 [3.25-6.01]) and three independent validation cohorts (Validation cohort-1: p < 0.01, HR [95%CI] = 1.70 [1.15-2.51]; Validation cohort-2: p < 0.001, HR [95% CI] = 2.30 [1.67-3.16]; Validation cohort-3: p < 0.01, HR [95% CI] = 2.42 [1.25-4.70]). After adjusting for known clinicopathological factors, multivariate cox analysis confirmed the ISE signature's independent prognostic value. Subgroup analysis found that stage III patients with low ISE score might benefit from adjuvant chemotherapy (p < 0.001, HR [95%CI] = 0.15 [0.04-0.55]). Hypergeometric test and enrichment analysis revealed that low-risk group was enriched in thr immune pathway while high-risk group was associated with the EMT pathway and CMS4 subtype. CONCLUSION We proposed an ISE signature for robustly predicting the recurrence of stage II/III CRC and help treatment decision by identifying patients who will not benefit from current standard treatment.
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Affiliation(s)
- Du Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Wang
- Department of Clinical Laboratory, Haining People's Hospital, Jiaxing, China
| | - Min-Er Zhong
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dejun Fan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuanhui Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cheng-Hang Li
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ze-Ping Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiqi Zhu
- Department of Colorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Min-Yi Lv
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chuling Hu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Duan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiao-Jian Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Feng Gao
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Stem Cells for Cancer Therapy: Translating the Uncertainties and Possibilities of Stem Cell Properties into Opportunities for Effective Cancer Therapy. Int J Mol Sci 2023; 24:ijms24021012. [PMID: 36674525 PMCID: PMC9864033 DOI: 10.3390/ijms24021012] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
Cancer recurrence and drug resistance following treatment, as well as metastatic forms of cancer, are trends that are commonly encountered in cancer management. Amidst the growing popularity of personalized medicine and targeted therapy as effective cancer treatment, studies involving the use of stem cells in cancer therapy are gaining ground as promising translational treatment options that are actively pursued by researchers due to their unique tumor-homing activities and anti-cancer properties. Therefore, this review will highlight cancer interactions with commonly studied stem cell types, namely, mesenchymal stroma/stem cells (MSC), induced pluripotent stem cells (iPSC), iPSC-derived MSC (iMSC), and cancer stem cells (CSC). A particular focus will be on the effects of paracrine signaling activities and exosomal miRNA interaction released by MSC and iMSCs within the tumor microenvironment (TME) along with their therapeutic potential as anti-cancer delivery agents. Similarly, the role of exosomal miRNA released by CSCs will be further discussed in the context of its role in cancer recurrence and metastatic spread, which leads to a better understanding of how such exosomal miRNA could be used as potential forms of non-cell-based cancer therapy.
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He X, Chen H, Zhong X, Wang Y, Hu Z, Huang H, Zhao S, Wei P, Shi D, Li D. BST2 induced macrophage M2 polarization to promote the progression of colorectal cancer. Int J Biol Sci 2023; 19:331-345. [PMID: 36594082 PMCID: PMC9760448 DOI: 10.7150/ijbs.72538] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Tumor-associated macrophages (TAMs) are one of the most prominent tumor-infiltrating immune cells in the tumor microenvironment (TME) of CRC and play a vital role in the progression of CRC. BST2 was predicted to be associated with the infiltration of TAMs. However, its potential function by which CRC cells and TAMs interact with each other still needs further investigation. Methods: The target genes in CRC were selected by bioinformatics screening. The level of bone marrow stromal cell antigen 2 (BST2) in CRC cells and tissues was determined by qRT‒PCR, Western blotting, and immunohistochemistry staining. In vitro and in vivo assays were applied to clarify the function of BST2. Results: In this study, according to bioinformatics analysis, a nomogram based on the risk score (constructed by BST2 and CAV1 (caveolin-1)) and clinical features was built and displayed satisfactory prognostic value. Upregulated BST2 was significantly related to Braf mutation, dMMR/MSI-H, CMS1 subtype, and immune response and was a potential biomarker for predicting immune checkpoint blockade therapy. Silencing BST2 in CRC obviously restrained CRC progression and M2 TAM polarization. The infiltration of TAMs was positively correlated with the high expression of BST2, and depletion of TAMs alleviated the protumoural effect of BST2 in CRC in vivo. In vitro experiments revealed that a reduction in BST2 in CRC inhibited CRC proliferation and migration and also M2 polarization. Conclusion: These findings indicated that BST2 played a vital role in CRC progression and might be a predictable marker for immunotherapy.
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Affiliation(s)
- Xuefeng He
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Huaijun Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyang Zhong
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Yaxian Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Zijuan Hu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China,Institute of Pathology, Fudan University, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Huixia Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China,Institute of Pathology, Fudan University, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Senlin Zhao
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Ping Wei
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China,Institute of Pathology, Fudan University, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China,✉ Corresponding authors: Dawei Li, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Debing Shi, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Ping Wei, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Debing Shi
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China,✉ Corresponding authors: Dawei Li, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Debing Shi, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Ping Wei, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China,✉ Corresponding authors: Dawei Li, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Debing Shi, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Ping Wei, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
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Huang B, Lang X, Li X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol 2022; 12:1023177. [PMID: 36591515 PMCID: PMC9800921 DOI: 10.3389/fonc.2022.1023177] [Citation(s) in RCA: 173] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation. It can activate janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. As one of the important signal transduction pathways in cells, JAK2/STAT3 signaling pathway plays a critical role in cell proliferation and differentiation by affecting the activation state of downstream effector molecules. The activation of JAK2/STAT3 signaling pathway is involved in tumorigenesis and development. It contributes to the formation of tumor inflammatory microenvironment and is closely related to the occurrence and development of many human tumors. This article focuses on the relationship between IL-6/JAK2/STAT3 signaling pathway and liver cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, pancreatic cancer and ovarian cancer, hoping to provide references for the research of cancer treatment targeting key molecules in IL-6/JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Bei Huang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Xiaoling Lang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
| | - Xihong Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,Emergency Department, West China Second University Hospital, Sichuan University, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
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Anti-Tumor Effects of Engineered VNP20009-Abvec-Igκ-mPD-1 Strain in Melanoma Mice via Combining the Oncolytic Therapy and Immunotherapy. Pharmaceutics 2022; 14:pharmaceutics14122789. [PMID: 36559282 PMCID: PMC9781615 DOI: 10.3390/pharmaceutics14122789] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
Programmed cell death protein 1/Programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors are the most promising treatments for malignant tumors currently, but the low response rate limits their further clinical utilization. To address this problem, our group constructed an engineered strain of VNP20009-Abvec-Igκ-mPD-1 [V-A-mPD-1 (mPD-1, murine PD-1)] to combine oncolytic bacterial therapy with immunotherapy. Further, we evaluated its growth performance and mPD-1 expression ability in vitro while establishing the melanoma mice model to explore its potential anti-cancer effects in tumor therapy. Our results indicated that the V-A-mPD-1 strain has superior growth performance and can invade B16F10 melanoma cells and express PD-1. In addition, in the melanoma mice model, we observed a marked reduction in tumor volume and the formation of a larger necrotic area. V-A-mPD-1 administration resulted in a high expression of mPD-1 at the tumor site, inhibiting tumor cell proliferation via the down-regulation of the expression of rat sarcoma (Ras), phosphorylated mitogen-activated protein kinase (p-MEK)/MEK, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK expression significantly inhibited tumor cell proliferation. Tumor cell apoptosis was promoted by down-regulating phosphoinositide 3 kinase (PI3K) and protein kinase B (AKT) signaling pathways, as evidenced by an increased Bcl-2-associated X protein/B cell lymphoma-2 (Bax/Bcl-2) expression ratio. Meanwhile, the expression levels of systemic inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), were substantially reduced. In conclusion, our research demonstrated that V-A-mPD-1 has an excellent anti-tumor effect, prompting that the combined application of microbial therapy and immunotherapy is a feasible cancer treatment strategy.
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Nuclear translocation of Gasdermin D sensitizes colorectal cancer to chemotherapy in a pyroptosis-independent manner. Oncogene 2022; 41:5092-5106. [PMID: 36245058 DOI: 10.1038/s41388-022-02503-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 09/29/2022] [Accepted: 10/06/2022] [Indexed: 11/08/2022]
Abstract
Gasdermin D (GSDMD) has recently been identified as a cytoplasmic effector protein that plays a central role in pyroptosis of immune cells. However, GSDMD is a universally expressed protein, and its function beyond pyroptosis, especially in cancer cells, has not been well characterized. Here, we report that predominant localization of GSDMD in the nucleoplasm in vivo indicates favorable clinical outcomes in colorectal cancer, while a lack of nuclear localization of GSDMD is associated with poor outcomes. Nuclear GSDMD, rather than cytoplasmic GSDMD, inhibits cell growth and promotes apoptosis in colorectal cancer. Hypoxia in the tumor microenvironment accounts for mild or moderate nuclear translocation of GSDMD in vivo. Under the stimulation of chemotherapy drugs, nuclear GSDMD promotes apoptosis via regulation of its subcellular distribution rather than pyroptosis-related cleavage. After nuclear translocation, GSDMD interacts with PARP-1 to dramatically inhibit its DNA damage repair-related function by functioning like the PARP inhibitor olaparib, thus forming a "hypoxia/chemotherapy-GSDMD nuclear translocation-PARP-1 blockade-DNA damage and apoptosis" axis. This study redefines the pyroptosis-independent function of GSDMD and suggests that the subcellular localization of GSDMD may serve as a molecular indicator of clinical outcomes and a promising therapeutic target in colorectal cancer.
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Yu L, Zhang MM, Hou JG. Molecular and cellular pathways in colorectal cancer: apoptosis, autophagy and inflammation as key players. Scand J Gastroenterol 2022; 57:1279-1290. [PMID: 35732586 DOI: 10.1080/00365521.2022.2088247] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal carcinogenesis (CRC) is one of the most aggressive forms of cancer, particularly in developing countries. It accounts for the second and third-highest reason for cancer-induced lethality in women and men respectively. CRC involves genetic and epigenetic modifications in colonic epithelium, leading to colon adenocarcinoma. The current review highlights the pathogenic mechanisms and multifactorial etiology of CRC, influenced by apoptosis, inflammation, and autophagy pathways. METHODS We have carried out a selective literature review on mechanisms contributing to the pathogenesis of CRC. RESULTS Resistance to senescence and apoptosis of the mesenchymal cells, which play a key role in intestinal organogenesis, morphogenesis and homeostasis, appears important for sporadic CRC. Additionally, inflammation-associated tumorigenesis is a key incident in CRC, supported by immune disruptors, adaptive and innate immune traits, environmental factors, etc. involving oxidative stress, DNA damage and epigenetic modulations. The self-digesting mechanism, autophagy, also plays a twin role in CRC through the participation of LC3/LC3-II, Beclin-1, ATG5, other autophagy proteins, and Inflammatory Bowel Disease (IBD) susceptibility genes. It facilitates the promotion of effective surveillance pathways and stimulates the generation of malignant tumor cells. The autophagy and apoptotic pathways undergo synergistic or antagonistic interactions in CRC and bear a critical association with IBD that results from the pro-neoplastic effects of persistent intestinal inflammation. Conversely, pro-inflammatory factors stimulate tumor growth and angiogenesis and inhibit apoptosis, suppressing anti-tumor activities. CONCLUSION Hence, research attempts for the development of potential therapies for CRC are in progress, primarily based on combinatorial approaches targeting apoptosis, inflammation, and autophagy.
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Affiliation(s)
- Lei Yu
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Miao-Miao Zhang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Ji-Guang Hou
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
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Jakab A, Patai ÁV, Micsik T. Digital image analysis provides robust tissue microenvironment-based prognosticators in patients with stage I-IV colorectal cancer. Hum Pathol 2022; 128:141-151. [PMID: 35820451 DOI: 10.1016/j.humpath.2022.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/03/2022] [Accepted: 07/02/2022] [Indexed: 11/26/2022]
Abstract
In patients with colorectal cancer (CRC), a promising marker is tumor-stroma ratio (TSR). Quantification issues highlight the importance of precise assessment that might be solved by artificial intelligence-based digital image analysis systems. Some alternatives have been offered so far, although these platforms are either proprietary developments or require additional programming skills. Our aim was to validate a user-friendly, commercially available software running in everyday computational environment to improve TSR assessment and also to compare the prognostic value of assessing TSR in 3 distinct regions of interests, like hotspot, invasive front, and whole tumor. Furthermore, we compared the prognostic power of TSR with the newly suggested carcinoma percentage (CP) and carcinoma-stroma percentage (CSP). Slides of 185 patients with stage I-IV CRC with clinical follow-up data were scanned and evaluated by a senior pathologist. A machine learning-based digital pathology software was trained to recognize tumoral and stromal compartments. The aforementioned parameters were evaluated in the hotspot, invasive front, and whole tumor area, both visually and by machine learning. Patients were classified based on TSR, CP, and CSP values. On multivariate analysis, TSR-hotspot was found to be an independent prognostic factor of overall survival (hazard ratio for TSR-hotspotsoftware: 2.005 [95% confidence interval (CI): 1.146-3.507], P = .011, for TSR-hotspotvisual: 1.781 [CI: 1.060-2.992], P = .029). Also, TSR was an independent predictor for distant metastasis and local relapse in most settings. Generally, software performance was comparable to visual evaluation and delivered reliable prognostication in more settings also with CP and CSP values. This study presents that software-assisted evaluation is a robust prognosticator. Our approach used a less sophisticated and thus easily accessible software without the aid of a convolutional neural network; however, it was still effective enough to deliver reliable prognostic information.
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Affiliation(s)
- Anna Jakab
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Üllői őt 26, H-1085, Hungary; Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Üllői út 78, H-1082, Hungary.
| | - Árpád V Patai
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Üllői út 78, H-1082, Hungary; Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Üllői út 78, H-1082, Hungary
| | - Tamás Micsik
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Üllői őt 26, H-1085, Hungary; Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Üllői út 78, H-1082, Hungary; Saint George Teaching Hospital of Fejér County, Székesfehérvár, Seregélyesi út 3, HU-8000, Hungary
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Shi Y, Yasui M, Hara-Chikuma M. AQP9 transports lactate in tumor-associated macrophages to stimulate an M2-like polarization that promotes colon cancer progression. Biochem Biophys Rep 2022; 31:101317. [PMID: 35967760 PMCID: PMC9372591 DOI: 10.1016/j.bbrep.2022.101317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/04/2022] [Accepted: 07/15/2022] [Indexed: 11/18/2022] Open
Abstract
Macrophages play a major role in the immune defense against pathogenic factors; however, they can lead to tumor exacerbation and metastasis, as the tumor microenvironment (TME) polarizes tumor-associated macrophages (TAMs) into the M2 subtype. Lactate, a metabolite produced by carcinoma cells at high concentrations in the TME, induces an M2-polarization in macrophages, which ultimately leads to the secretion of factors, such as vascular endothelial growth factor (VEGF), and promotes tumor progression. However, the effect of TAM lactate import on tumor progression has not been fully elucidated. Aquaporin 9 (AQP9) is a transporter of water and glycerol expressed in macrophages. Here, we used a tumor allograft mouse model to show that AQP9 knockout (AQP9−/−) mice were more resistant against tumor cell growth and exhibited a suppressive M2-like polarization in tumor tissue than wild-type mice. Moreover, we discovered that the primary bone marrow-derived macrophages from AQP9−/− mice were less sensitive to lactate stimulation and exhibited reduced M2-like polarization as well as decreased VEGF production. To further investigate the role of AQP9 in macrophage polarization, we overexpressed AQP9 in Chinese hamster ovary cells and found that AQP9 functioned in lactate import. In contrast, primary AQP9−/− macrophages and AQP9 knockdown RAW264.7 cells exhibited a reduced lactate transport rate, suggesting the involvement of AQP9 in lactate transport in macrophages. Together, our results reveal the mechanism by which the TME modifies the polarization and function of tumor-infiltrating macrophages via AQP9 transport function.
Tumor growth was suppressed in AQP9-deficient mice. M2-like TAMs were reduced in tumor tissues of AQP9-deficient mice. AQP9 deficiency attenuated lactate-induced M2 polarization in macrophages. AQP9 is a lactate transporter in macrophages.
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Affiliation(s)
- Yundi Shi
- Department of Pharmacology, Keio University School of Medicine, Japan
| | - Masato Yasui
- Department of Pharmacology, Keio University School of Medicine, Japan
- Center for Water Biology and Medicine, Keio University Global Research Institute, Japan
| | - Mariko Hara-Chikuma
- Department of Pharmacology, Keio University School of Medicine, Japan
- Corresponding author. Department of Pharmacology, Keio University, School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160, Japan.
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Wang Y, Zhang Z, Sun W, Zhang J, Xu Q, Zhou X, Mao L. Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets. Biomed Pharmacother 2022; 153:113524. [PMID: 36076606 DOI: 10.1016/j.biopha.2022.113524] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 01/17/2023] Open
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Melia F, Udomjarumanee P, Zinovkin D, Arghiani N, Pranjol MZI. Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer. Front Oncol 2022; 12:975644. [PMID: 36059680 PMCID: PMC9434004 DOI: 10.3389/fonc.2022.975644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/01/2022] [Indexed: 12/04/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence.
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Affiliation(s)
- Francesco Melia
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - Palita Udomjarumanee
- Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Dmitry Zinovkin
- Department of Pathology, Gomel State Medical University, Gomel, Belarus
| | - Nahid Arghiani
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
- Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- *Correspondence: Nahid Arghiani, ; Md Zahidul Islam Pranjol,
| | - Md Zahidul Islam Pranjol
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
- *Correspondence: Nahid Arghiani, ; Md Zahidul Islam Pranjol,
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Ramuta TŽ, Kreft ME. Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells. Cancers (Basel) 2022; 14:cancers14153761. [PMID: 35954425 PMCID: PMC9367361 DOI: 10.3390/cancers14153761] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Tumours consist of different cell types and an extracellular matrix, all of which together form a complex microenvironment. The tumour microenvironment plays a critical role in various aspects of tumour development and progression. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that have a tri-lineage differentiation capacity and are one of the key stromal cells in the tumour microenvironment. Following the interaction with cancer cells, they are transformed from naïve MSCs to tumour-associated MSCs, which substantially affect tumour growth and progression as well as the development of chemoresistance in cancer cells. The aim of this review article is to provide an overview of studies that have investigated how MSCs affect the susceptibility of cancer cells to chemotherapeutics. Their results show that MSCs protect cancer cells from chemotherapeutics by influencing several signalling pathways. This knowledge is crucial for the development of new treatment approaches that will lead to improved treatment outcomes. Abstract The tumour microenvironment, which is comprised of various cell types and the extracellular matrix, substantially impacts tumour initiation, progression, and metastasis. Mesenchymal stem/stromal cells (MSCs) are one of the key stromal cells in the tumour microenvironment, and their interaction with cancer cells results in the transformation of naïve MSCs to tumour-associated MSCs. The latter has an important impact on tumour growth and progression. Recently, it has been shown that they can also contribute to the development of chemoresistance in cancer cells. This review provides an overview of 42 studies published between 1 January 2001 and 1 January 2022 that examined the effect of MSCs on the susceptibility of cancer cells to chemotherapeutics. The studies showed that MSCs affect various signalling pathways in cancer cells, leading to protection against chemotherapy-induced damage. Promising results emerged from the use of inhibitors of various signalling pathways that are affected in cancer cells due to interactions with MSCs in the tumour microenvironment. These studies present a good starting point for the investigation of novel treatment approaches and demonstrate the importance of targeting the stroma in the tumour microenvironment to improve treatment outcomes.
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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Matsubara Y, Ota Y, Tanaka Y, Denda T, Hijikata Y, Boku N, Lim LA, Hirata Y, Tsurita G, Adachi E, Yotsuyanagi H. Altered mucosal immunity in HIV-positive colon adenoma: decreased CD4 + T cell infiltration is correlated with nadir but not current CD4 + T cell blood counts. Int J Clin Oncol 2022; 27:1321-1330. [PMID: 35643870 DOI: 10.1007/s10147-022-02188-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/06/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND People living with HIV (PLWH) face greater risks of developing non-AIDS-defining cancers (NADCs) than the general population; however, the underlying mechanisms remain elusive. The tumor microenvironment plays a significant role in the carcinogenesis of colorectal cancer (CRC), an NADC. We studied this carcinogenesis in PLWH by determining inflammatory phenotypes and assessing PD-1/PD-L1 expression in premalignant CRC stages of colon adenomas in HIV-positive and HIV-negative patients. METHODS We obtained polyp specimens from 22 HIV-positive and 61 HIV-negative participants treated with colonoscopy and polyp excision. We analyzed adenomas from 33 HIV-positive and 99 HIV-negative patients by immunohistochemistry using anti-CD4, anti-CD8, anti-FoxP3, and anti-CD163 antibodies. Additionally, we analyzed the expression levels of immune checkpoint proteins. We also evaluated the correlation between cell infiltration and blood cell counts. RESULTS HIV-positive participants had fewer infiltrating CD4+ T cells than HIV-negative participants (p = 0.0016). However, no statistical differences were observed in infiltrating CD8+ and FoxP3+ T cells and CD163+ macrophages. Moreover, epithelial cells did not express PD-1 or PD-L1. Notably, CD4+ T cell infiltration correlated with nadir blood CD4+ T cell counts (p < 0.05) but not with current blood CD4+ T cell counts. CONCLUSION Immune surveillance dysfunction owing to decreased CD4+ T cell infiltration in colon adenomas might be involved in colon carcinogenesis in HIV-positive individuals. Collectively, since the nadir blood CD4+ T cell count is strongly correlated with CD4+ T cell infiltration, it could facilitate efficient follow-up and enable treatment strategies for HIV-positive patients with colon adenomas.
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Affiliation(s)
- Yasuo Matsubara
- Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
| | - Yasunori Ota
- Department of Diagnostic Pathology, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Yukihisa Tanaka
- Department of Diagnostic Pathology, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Tamami Denda
- Department of Diagnostic Pathology, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Yasuki Hijikata
- Department of Palliative Medicine/Advanced Clinical Oncology, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Narikazu Boku
- Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Lay Ahyoung Lim
- Department of Research, Kitasato Institute Hospital, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8642, Japan
| | - Yoshihiro Hirata
- Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Giichiro Tsurita
- Department of Surgery, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of the Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Hiroshi Yotsuyanagi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of the Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
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Gilazieva Z, Ponomarev A, Rizvanov A, Solovyeva V. The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis. BIOLOGY 2022; 11:biology11060813. [PMID: 35741334 PMCID: PMC9220333 DOI: 10.3390/biology11060813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Simple Summary Extracellular vesicles (EVs) are membrane structures that play the role of intermediaries between tumor cells and the tumor microenvironment (TME) because they have the ability to transport lipids, transcription factors, mRNA, and proteins. Mesenchymal stem cells (MSCs) are a major component of the TME and may have different effects on tumor progression using EVs. This review includes information about various studies which have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. It provides an overview of the published data on EV MSCs and their effect on tumor cells. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described. Abstract Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play an important role in tumor progression. MSCs remodel the extracellular matrix, participate in the epithelial–mesenchymal transition, promote the spread of metastases, and inhibit antitumor immune responses in the TME; however, there are also data pertaining to the antitumor effects of MSCs. MSCs activate the cell death mechanism by modulating the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors, and proapoptotic proteins. One of the main ways in which MSCs and TME interact is through the production of extracellular vesicles (EVs) by cells. Currently, data on the effects of both MSCs and their EVs on tumor cells are rather contradictory. Various studies have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. In this review, we discuss published data on EV MSCs and their effect on tumor cells. The molecular composition of vesicles obtained from MSCs is also presented in the review. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.
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Luo W, Xiang W, Gan L, Che J, Li J, Wang Y, Han L, Gu R, Ye L, Wang R, Zhang X, Xu Y, Dai W, Mo S, Li Q, Cai G. Bulk and single-cell transcriptome profiling reveal necroptosis-based molecular classification, tumor microenvironment infiltration characterization, and prognosis prediction in colorectal cancer. J Transl Med 2022; 20:235. [PMID: 35590418 PMCID: PMC9118791 DOI: 10.1186/s12967-022-03431-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Background Necroptosis is a new form of programmed cell death that is associated with cancer initiation, progression, immunity, and chemoresistance. However, the roles of necroptosis-related genes (NRGs) in colorectal cancer (CRC) have not been explored comprehensively. Methods In this study, we obtained NRGs and performed consensus molecular subtyping by “ConsensusClusterPlus” to determine necroptosis-related subtypes in CRC bulk transcriptomic data. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of different cell types in the tumor microenvironment (TME). Single-cell transcriptomic analysis was performed to confirm classification related to NRGs. NRG_score was developed to predict patients’ survival outcomes with low-throughput validation in a patients’ cohort from Fudan University Shanghai Cancer Center. Results We identified three distinct necroptosis-related classifications (NRCs) with discrepant clinical outcomes and biological functions. Characterization of TME revealed that there were two stable necroptosis-related phenotypes in CRC: a phenotype characterized by few TME cells infiltration but with EMT/TGF-pathways activation, and another phenotype recognized as immune-excluded. NRG_score for predicting survival outcomes was established and its predictive capability was verified. In addition, we found NRCs and NRG_score could be used for patient or drug selection when considering immunotherapy and chemotherapy. Conclusions Based on comprehensive analysis, we revealed the potential roles of NRGs in the TME, and their correlations with clinicopathological parameters and patients’ prognosis in CRC. These findings could enhance our understanding of the biological functions of necroptosis, which thus may aid in prognosis prediction, drug selection, and therapeutics development. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03431-6.
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Affiliation(s)
- Wenqin Luo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenqiang Xiang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lu Gan
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Center of Evidence-Based Medicine, Fudan University, Shanghai, China
| | - Ji Che
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jing Li
- Department of CyberKnife Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Yichao Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lingyu Han
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruiqi Gu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li Ye
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Renjie Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiuping Zhang
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Shaobo Mo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Comprehensive Analyses of Stromal-Immune Score-Related Competing Endogenous RNA Networks In Colon Adenocarcinoma. DISEASE MARKERS 2022; 2022:4235305. [PMID: 35607443 PMCID: PMC9124109 DOI: 10.1155/2022/4235305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/12/2022] [Accepted: 04/21/2022] [Indexed: 12/14/2022]
Abstract
Although recent clinical investigations emphasize the roles of myriad diversities of RNAs in stromal and immune components in the tumor microenvironment, especially in colon adenocarcinoma, however, analyses of “competing endogenous RNAs (ceRNA)” network in association with stromal and immune scores have yet to be determined. This study was conducted to explore the regulatory mechanisms of a stromal-immune score-based ceRNA network in colon adenocarcinoma. Stromal and immune scores of colon adenocarcinoma tumor samples were calculated by using the ESTIMATE algorithm. Differential expression analysis between samples with high/low stromal and immune scores was performed, followed by functional annotation for the overlapping DEmRNAs. The ceRNA network was constructed by differential expression analysis, prediction of RNA-RNA interaction, and correlation with clinicopathological parameters of the patients, which were further verified by external datasets and experiments. Colon adenocarcinoma patients having higher immune scores exhibited prolonged overall survival. RNA dataset analyses from TCGA revealed aberrant expressions of a total of 2052 mRNAs, 108 lncRNAs, and 70 miRNAs between high and low stromal/immune groups. Functional annotation mapped the differentially overexpressed mRNAs for immune-associated GO terms. To construct the ceRNA network, a total of 48 lncRNAs, 40 miRNAs, and 199 mRNAs were sorted out. A dysregulated ceRNA network consisting of 6 lncRNAs, 11 miRNAs, and 39 mRNAs was constructed by comparing RNA expressions between cancer as well as adjacent normal tissues. The ceRNA regulatory axis “MIAT/miR-532-3p/STC1” was regarded as a potential hit by the comprehensive analysis. The RT-qPCR assay showed upregulation of MIAT and STC1 while downregulation of hsa-miR-532-3p expression in cancer. Thus, our study highlights the potential role of a stromal-immune score-based ceRNA network in the colon adenocarcinoma microenvironment. The ceRNA axis MIAT/miR-532-3p/STC1 could serve as a promising therapeutic target for colon adenocarcinoma.
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Brás MM, Sousa SR, Carneiro F, Radmacher M, Granja PL. Mechanobiology of Colorectal Cancer. Cancers (Basel) 2022; 14:1945. [PMID: 35454852 PMCID: PMC9028036 DOI: 10.3390/cancers14081945] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 11/16/2022] Open
Abstract
In this review, the mechanobiology of colorectal cancer (CRC) are discussed. Mechanotransduction of CRC is addressed considering the relationship of several biophysical cues and biochemical pathways. Mechanobiology is focused on considering how it may influence epithelial cells in terms of motility, morphometric changes, intravasation, circulation, extravasation, and metastization in CRC development. The roles of the tumor microenvironment, ECM, and stroma are also discussed, taking into account the influence of alterations and surface modifications on mechanical properties and their impact on epithelial cells and CRC progression. The role of cancer-associated fibroblasts and the impact of flow shear stress is addressed in terms of how it affects CRC metastization. Finally, some insights concerning how the knowledge of biophysical mechanisms may contribute to the development of new therapeutic strategies and targeting molecules and how mechanical changes of the microenvironment play a role in CRC disease are presented.
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Affiliation(s)
- Maria Manuela Brás
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; (M.M.B.); (S.R.S.); (F.C.); (P.L.G.)
- Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal
- Faculdade de Engenharia da Universidade do Porto (FEUP), 4200-465 Porto, Portugal
| | - Susana R. Sousa
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; (M.M.B.); (S.R.S.); (F.C.); (P.L.G.)
- Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal
- Instituto Superior de Engenharia do Porto (ISEP), Instituto Politécnico do Porto (IPP), 4200-072 Porto, Portugal
| | - Fátima Carneiro
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; (M.M.B.); (S.R.S.); (F.C.); (P.L.G.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-465 Porto, Portugal
- Serviço de Patologia, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal
- Faculdade de Medicina da Universidade do Porto (FMUP), 4200-319 Porto, Portugal
| | - Manfred Radmacher
- Institute for Biophysics, University of Bremen, 28334 Bremen, Germany
| | - Pedro L. Granja
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal; (M.M.B.); (S.R.S.); (F.C.); (P.L.G.)
- Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal
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Li L, Du X, Fan G. Identifying Potential Biomarkers of Prognostic Value in Colorectal Cancer via Tumor Microenvironment Data Mining. Front Genet 2022; 12:787208. [PMID: 35251116 PMCID: PMC8890124 DOI: 10.3389/fgene.2021.787208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/16/2021] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is a common cancer that has increased rapidly worldwide in the past decades with a relatively high mortality rate. An increasing body of evidence has highlighted the importance of infiltrating immune and stromal cells in CRC. In this study, based on gene expression data of CRC patients in TCGA database we evaluated immune and stromal scores in tumor microenvironment using ESTIMATE method. Results showed there was potential correlation between these scores and the prognosis, and that patients with higher immune score and lower stromal score had longer survival time. We found that immune score was correlated with clinical characteristics including tumor location, tumor stage, and survival time. Specifically, the right-sided colon cancer had markedly elevated immune score, compared to left-sided colon cancer and rectal cancer. These results might be useful for understanding tumor microenvironment in colorectal cancer. Through the differential analysis we got a list of genes significantly associated with immune and stromal scores. Gene Set Enrichment and protein-protein interaction network analysis were used to further illustrate these differentially expressed genes. Finally, 15 hub genes were identified, and three (CXCL9, CXCL10 and SELL) of them were validated with favorable outcomes in CRC patients. Our result suggested that these tumor microenvironment related genes might be potential biomarkers for the prognosis of CRC.
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Affiliation(s)
- Lei Li
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Qingdao, BGI-Shenzhen, Qingdao, China
| | - Xiao Du
- BGI-Qingdao, BGI-Shenzhen, Qingdao, China
- BGI-Shenzhen, Shenzhen, China
- *Correspondence: Guangyi Fan, ; Xiao Du,
| | - Guangyi Fan
- BGI-Qingdao, BGI-Shenzhen, Qingdao, China
- BGI-Shenzhen, Shenzhen, China
- *Correspondence: Guangyi Fan, ; Xiao Du,
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Wnt signaling pathway in cancer immunotherapy. Cancer Lett 2022; 525:84-96. [PMID: 34740608 DOI: 10.1016/j.canlet.2021.10.034] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/06/2021] [Accepted: 10/20/2021] [Indexed: 12/11/2022]
Abstract
Wnt/β-catenin signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. Dysregulation of the Wnt pathway is intricately involved in almost all stages of tumorigenesis in various cancers. Through direct and/or indirect effects on effector T cells, T-regulatory cells, T-helper cells, dendritic cells, and other cytokine-expressing immune cells, abnormal activation of Wnt/β-catenin signaling benefits immune exclusion and hinders T-cell-mediated antitumor immune responses. Activation of Wnt signaling results in increased resistance to immunotherapies. In this review, we summarize the process by which Wnt signaling affects cancer and immune surveillance, and the potential for targeting the Wnt-signaling pathway via cancer immunotherapy.
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Khalil HE, Ibrahim HIM, Ahmed EA, Emeka PM, Alhaider IA. Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a. Pharmaceuticals (Basel) 2022; 15:ph15020154. [PMID: 35215267 PMCID: PMC8876523 DOI: 10.3390/ph15020154] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/16/2022] [Accepted: 01/23/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer is a severe health condition and considered one of the major healthcare issues and is in need of innovative strategy for a cure. The current study aimed to investigate the chemical profile of Trigonella hamosa L. and a potential molecular approach to explain its regulation in cancer progression through an inflammatory mediator (COX-2) in A549 non-small lung cancer cell lines via in silico, mechanistic and molecular aspects. T. hamosa was extracted and then subjected to a CCK-8 cell viability assay in different cancer cell lines including MDA-MB-231, A549 and HCT-116. Total extract was subjected to several chromatographic techniques to yield orientin (OT); the structure was elucidated by inspection of NMR spectroscopic data. To achieve anticancer effects of OT, a cell viability assay using a CCK-8 kit, immunoprecipitation by Western blot, cell migration using a wound healing assay, cell invasion using a Matrigel-Transwell assay, apoptosis by AO/EB dual staining, flow cytometric analysis and DAPI staining, a silenced COX-2 model to determine PGE-2 production and real-time PCR and Western blot of BCL-2, CYP-1A1, iNOS and COX-2 markers were carried out. The results demonstrated that OT decreased the cell proliferation and controlled cell migration and invasive properties. OT destabilized the COX-2 mRNA and downregulated its expression in A549 cell lines. Virtual binding showed interaction (binding energy −10.43) between OT and COX-2 protein compared to the selective COX-2 inhibitor celecoxib (CLX) (binding energy −9.4). The OT-CLX combination showed a superior anticancer effect. The synergistic effect of OT-CLX combination was noticed in controlling the migration and invasion of A549 cell lines. OT-CLX downregulated the expression of BCL-2, iNOS and COX-2 and activated the proapoptotic gene CYP-1A1. OT mitigated the COX-2 expression via upregulation of miR-26b and miR-146a. Interestingly, COX-2-silenced transfected A549 cells exhibited reduced expression of miR-26b and miR-146a. The findings confirmed the direct interaction of OT with COX-2 protein. PGE-2 expression was quantified in both naïve and COX-2-silenced A549 cells. OT downregulated the release of PGE-2 in both tested conditions. These results confirmed the regulatory effect of OT on A549 cell growth in a COX-2-dependent manner. OT activated apoptosis via activation of CYP-1A1 expression in an independent manner. These results revealed that the OT-CLX combination could serve as a potential synergistic treatment for effective inflammatory-mediated anticancer strategies.
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Affiliation(s)
- Hany Ezzat Khalil
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (P.M.E.); (I.A.A.)
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
- Correspondence:
| | - Hairul-Islam Mohamed Ibrahim
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (H.-I.M.I.); (E.A.A.)
- Department of System Biology, Pondicherry Center for Biological Science and Educational Trust, Kottakuppam 605104, India
| | - Emad A. Ahmed
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (H.-I.M.I.); (E.A.A.)
- Lab of Molecular Physiology, Department of Zoology, Faculty of Science, Assiut University, Assiut 71515, Egypt
| | - Promise Madu Emeka
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (P.M.E.); (I.A.A.)
| | - Ibrahim A. Alhaider
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (P.M.E.); (I.A.A.)
- Research and Development, Saudi Food and Drug Authority, Riyadh 13312, Saudi Arabia
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Yue Y, Zhang Q, Sun Z. CX3CR1 Acts as a Protective Biomarker in the Tumor Microenvironment of Colorectal Cancer. Front Immunol 2022; 12:758040. [PMID: 35140706 PMCID: PMC8818863 DOI: 10.3389/fimmu.2021.758040] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) plays an important role in the pathogenesis of many cancers. We aimed to screen the TME-related hub genes of colorectal adenoma (CRAD) and identify possible prognostic biomarkers. The gene expression profiles and clinical data of 464 CRAD patients in The Cancer Genome Atlas (TCGA) database were downloaded. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was performed to calculate the ImmuneScore, StromalScore, and EstimateScore. Thereafter, differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein–protein interaction (PPI) analysis were performed to explore the roles of DEGs. Furthermore, univariate and multivariate Cox analyses were accomplished to identify independent prognostic factors of CRAD. CX3CR1 was selected as a hub gene, and the expression was confirmed in colorectal cancer (CRC) patients and cell lines. The correlations between CX3CR1 and tumor-infiltrating immune cells were estimated by Tumor IMmune Estimation Resource database (TIMER) and CIBERSORT analysis. Besides, we investigated the effects of coculture with THP-1-derived macrophages with HCT8 cells with low CX3CR1 expression on immune marker expression, cell viability, and migration. There were significant differences in the ImmuneScore and EstimateScore among different stages. Patients with low scores presented significantly lower lifetimes than those in the high-score group. Moreover, we recognized 1,578 intersection genes in ImmuneScore and StromalScore, and these genes were mainly enriched in numerous immune-related biological processes. CX3CR1 was found to be associated with immune cell infiltration levels, immune marker expression, and macrophage polarization. Simultaneous silencing of CX3CR1 and coculture with THP-1 cells further regulated macrophage polarization and promoted the cell proliferation and migration of CRC cells. CX3CR1 was decreased in CRAD tissues and cell lines and was related to T and N stages, tumor differentiation, and prognosis. Our results suggest that CX3CR1 contributes to the recruitment and regulation of immune-infiltrating cells and macrophage polarization in CRC and TAM-induced CRC progression. CX3CR1 may act as a prognostic biomarker in CRC.
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Affiliation(s)
- Yuanyi Yue
- Department of Gastroenterology Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiang Zhang
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhengrong Sun
- BioBank, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Zhengrong Sun,
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Yin J, Wang H, Hong Y, Ren A, Wang H, Liu L, Zhao Q. Identification of an at-risk subpopulation with high immune infiltration based on the peroxisome pathway and TIM3 in colorectal cancer. BMC Cancer 2022; 22:44. [PMID: 34996408 PMCID: PMC8739708 DOI: 10.1186/s12885-021-09085-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 11/29/2021] [Indexed: 12/17/2022] Open
Abstract
Background Peroxisomes are pivotal metabolic organelles that exist in almost all eukaryote cells. A reduction in numbers and enzymatic activities of peroxisomes was found in colon adenocarcinomas. However, the role of peroxisomes or the peroxisome pathway in colorectal cancer (CRC) is not defined. Methods In the current study, a peroxisome score was calculated to indicate the activity of the peroxisome pathway using gene set variant analysis based on transcriptomic datasets. CIBERSORTx was chosen to infer enriched immune cells for tumors among subgroups. The SubMap algorithm was applied to predict its sensitivity to immunotherapy. Results The patients with a relatively low peroxisome score and high level of T-cell immunoglobulin and mucin domain 3 (TIM-3) presented the worse overall survival than others. Moreover, low peroxisome scores were associated with high infiltration of lymphocytes and poor prognosis in those CRC patients. Thus, a PERLowTIM3High CRC risk subpopulation was identified and characterized by high immune infiltration. The results also showed that CD8 T cells and macrophages highly infiltrated tumors of the PERLowTIM3High group, regardless of consortium molecular subtype and microsatellite instability status. This subgroup had the highest tumor mutational burden and overexpression of immune checkpoint genes. Further, the PERLowTIM3High group showed a higher probability of responding to programmed cell death protein-1-based immunotherapy. In addition, genes involved in peroxisomal metabolic processes in CRC were also investigated since peroxisome is a rather pleiotropic and highly metabolic organelle in cell. The results indicated that only those genes involved in fatty acid alpha oxidation could be used to stratify CRC patients as similar as peroxisome pathway genes. Conclusions We revealed the favorable prognostic value of the peroxisome pathway in CRC and provided a new CRC stratification based on peroxisomes and TIM3, which might be helpful for CRC diagnostics and personalized treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-09085-9.
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Affiliation(s)
- Jinwen Yin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000, China
| | - Hao Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000, China
| | - Yuntian Hong
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.,Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China
| | - Anli Ren
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000, China
| | - Haizhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China. .,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000, China.
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China. .,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000, China.
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