|
1
|
Munhoz J, Newell M, Goruk S, Ghosh S, Patel D, Joy AA, Bigras G, Mazurak V, Courneya KS, Hemmings DG, Field CJ. Docosahexaenoic acid (DHA) supplementation attenuates changes in the concentration, phenotype, and response of immune peripheral blood cells in breast cancer patients undergoing neoadjuvant therapy. Secondary findings from the DHA-WIN trial. Breast Cancer Res 2025; 27:91. [PMID: 40405290 PMCID: PMC12100857 DOI: 10.1186/s13058-025-02048-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Accepted: 05/16/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Breast cancer neoadjuvant therapy may negatively impact the immune system. As a secondary outcome of the docosahexaenoic acid (DHA) for women with breast cancer in the neoadjuvant setting (DHA-WIN trial), we sought to assess the effects of an intervention with DHA on parameters of immune function of women undergoing neoadjuvant therapy. METHODS Women with early-stage breast cancer in the neoadjuvant setting were recruited for the DHA-WIN trial and randomly assigned to receive either 4.4 g/day of DHA or a placebo for 18 weeks in conjunction with their neoadjuvant chemotherapy for breast cancer. Venous blood was collected to isolate peripheral blood mononuclear cells. Immune parameters were assessed by measuring white blood cell concentration, flow cytometry, and cytokines concentration after mitogen-stimulated immune response. RESULTS In the placebo group the proportion of T cells (CD3 +), and functionally active monocytes (CD14 + HLA-DR +) was reduced at the last cycle of chemotherapy (15 weeks) but remained constant in the DHA group (P interaction < 0.05). The neutrophil-to-lymphocyte ratio (NLR) was maintained in the DHA group but increased in the placebo at the end of chemotherapy (P-interaction = 0.02). An increase in this ratio was associated with lower chance of achieving pathological complete response (OR = 0.32, 95% CI [0.14,0.16], P = 0.01). After 15 weeks of therapy, the DHA-supplemented group had higher concentrations of stimulated cytokines IL-4, IL-10, and the T helper type 1 cytokine IFN-γ after phytohemagglutinin (PHA) challenge, and higher concentrations of TNF-α and IFN-γ cytokines after lipopolysaccharide exposure (P < 0.05). CONCLUSION Supplementing DHA during breast cancer neoadjuvant chemotherapy improved systemic immune function by attenuating changes in blood cell concentrations, preventing depletion of immune cells, and enhancing ex vivo cytokine secretion after stimulation.
Collapse
Affiliation(s)
- Jaqueline Munhoz
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Marnie Newell
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Susan Goruk
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton, T6G 1Z2, Canada
- Department of Public Health Sciences, Henry Ford Hospital, Detroit, USA
| | - Dhruvesh Patel
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Anil Abraham Joy
- Department of Oncology, University of Alberta, Edmonton, T6G 1Z2, Canada
| | - Gilbert Bigras
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Vera Mazurak
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Kerry S Courneya
- Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, T6G 2H9, Canada
| | - Denise G Hemmings
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T5G 0B6, Canada
| | - Catherine J Field
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
| |
Collapse
|
|
2
|
Jiang F, Yao C. Nomograms for predicting risk and prognosis of liver metastases in ovarian cancer patients. J Gynecol Obstet Hum Reprod 2025; 54:102918. [PMID: 39892518 DOI: 10.1016/j.jogoh.2025.102918] [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: 11/27/2024] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/03/2025]
Abstract
AIMS Liver metastases (LiM) commonly manifest in ovarian cancer (OC) patients. We intended to establish nomograms for predicting the risk and prognostic factors in OCLiM patients. METHODS Data from the SEER database (Nov 2022, Sub 1992-2020) were analyzed, excluding patients with missing data on liver metastases, survival months, race, AJCC T stage, marital status, rural/urban status, and metastases to bone, brain, or lung. Logistic and Cox regression analyses identified risk and prognostic factors for liver metastases. Predictive nomograms were developed from the multivariable regression results. The nomograms were evaluated using Harrell's C-index, ROC curve, calibration curve, DCA, NRI, and IDI. Moreover, the efficacy of the treatment in the new risk stratification subgroups was demonstrated by Kaplan-Meier (KM) curves. RESULTS Among 17,056 OC patients, 5.67% (n = 967) had liver metastases. Nomograms were constructed based on identified risk and prognostic factors, with dynamic web-based nomograms developed for clinical use. The nomogram demonstrated C-index values of 81.9% (training) and 82.9% (validation) for predicting liver metastases. For OS and CSS, the C-index values were 73.3% and 73.7% (training), and 73.3% and 72.8% (validation), respectively. The ROC curves for OS at 1-, 3-, 5-year showed AUC values of 84.1%, 79.8%, 75.9% (training) and 82.9%, 78.5%, 82.2% (validation), respectively. For CSS, AUC values at 1-, 3-, and 5-year were 84.5%, 80.2%, 76.1% (training) and 82.6%, 78.0, 82.0% (validation), respectively. The calibration and DCA curves confirmed favorable performance. NRI and IDI analyses showed superiority over the Grade and AJCC stage systems. Surgery improved prognosis in the low-risk group, while chemotherapy was more effective in both low- and medium-risk groups. CONCLUSIONS we developed nomograms and risk stratification systems to assist clinicians in the individualized prediction, risk stratification, and prognostic assessment of OCLiM patients.
Collapse
Affiliation(s)
- Feng Jiang
- Center of Clinical Laboratory, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, 215000, Jiangsu, PR China
| | - Chunfang Yao
- Department of Pathology, Children's Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou, 215000, Jiangsu, PR China.
| |
Collapse
|
|
3
|
Rastegar-Pouyani N, Farzin MA, Zafari J, Haji Abdolvahab M, Hassani S. Repurposing the anti-parasitic agent pentamidine for cancer therapy; a novel approach with promising anti-tumor properties. J Transl Med 2025; 23:258. [PMID: 40033361 PMCID: PMC11877826 DOI: 10.1186/s12967-025-06293-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/23/2025] [Indexed: 03/05/2025] Open
Abstract
Pentamidine (PTM) is an aromatic diamidine administered for infectious diseases, e.g. sleeping sickness, malaria, and Pneumocystis jirovecii pneumonia. Due to similarities of cellular mechanisms between human cells and such infections, PTM has also been proposed for repurposing in non-infectious diseases such as cancer. Indeed, by modulating different signaling pathways such as PI3K/AKT, MAPK/ERK, p53, PD-1/PD-L1, etc., PTM has been shown to inhibit different properties of cancer, including proliferation, invasion, migration, hypoxia, and angiogenesis, while inducing anti-tumor immune responses and apoptosis. Given the promising implications of PTM for cancer treatment, however, the clinical translation of PTM in cancer is not without certain challenges. In fact, clinical trials have shown that systemic administration of PTM can be concurrent with serious adverse effects, e.g. hypoglycemia. Therefore, to reduce the administered doses of PTM, lower the risk of adverse effects, and prevent any potential drug resistance, while maintaining the anti-tumor efficacy, two main strategies have been suggested. One is combination therapy that employs PTM in conjunction with other anti-cancer modalities, such as chemotherapy and radiotherapy, and attacks tumor cells with significant additive or synergistic anti-tumor effects. The other is developing PTM-loaded nanocarrier drug delivery systems e.g. pegylated liposomes, chitosan-coated niosomes, squalene-based nanoparticles, hyaluronated lipid-polymer hybrid nanoparticles, etc., that offer enhanced pharmacokinetic characteristics, including increased bioavailability, sit-targeting, and controlled/sustained drug release. This review highlights the anti-tumor properties of PTM that favor its repurposing for cancer treatment, as well as, PTM-based combination therapies and nanocarrier delivery systems which can enhance therapeutic efficacy and simultaneously reduce toxicity.
Collapse
Affiliation(s)
- Nima Rastegar-Pouyani
- Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran.
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Mohammad Amin Farzin
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Jaber Zafari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohadeseh Haji Abdolvahab
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Shokoufeh Hassani
- Toxicology and Diseases Specialty Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
4
|
Kantapan J, Innuan P, Kongkarnka S, Sangthong P, Dechsupa N. Pentagalloyl Glucose from Bouea macrophylla Suppresses the Epithelial-Mesenchymal Transition and Synergizes the Doxorubicin-Induced Anticancer and Anti-Migration Effects in Triple-Negative Breast Cancer. Pharmaceuticals (Basel) 2024; 17:1729. [PMID: 39770571 PMCID: PMC11679756 DOI: 10.3390/ph17121729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/11/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Triple-negative breast cancer (TNBC) represents an aggressive form of breast cancer with few available therapeutic options. Chemotherapy, particularly with drugs like doxorubicin (DOX), remains the cornerstone of treatment for this challenging subtype. However, the clinical utility of DOX is hampered by adverse effects that escalate with higher doses and drug resistance, underscoring the need for alternative therapies. This study explored the efficacy of pentagalloyl glucose (PGG), a natural polyphenol derived from Bouea macrophylla, in enhancing DOX's anticancer effects and suppressing the epithelial-mesenchymal transition (EMT) in TNBC cells. Methods: This study employed diverse methodologies to assess the effects of PGG and DOX on TNBC cells. MDA-MB231 triple-negative breast cancer cells were used to evaluate cell viability, migration, invasion, apoptosis, mitochondrial membrane potential, and protein expression through techniques including MTT assays, wound healing assays, flow cytometry, Western blotting, and immunofluorescence. Results: Our findings demonstrate that PGG combined with DOX significantly inhibits TNBC cell proliferation, migration, and invasion. PGG enhances DOX-induced apoptosis by disrupting the mitochondrial membrane potential and activating caspase pathways; consequently, the activation of caspase-3 and the cleavage of PARP are increased. Additionally, the study shows that the combination treatment upregulates ERK signaling, further promoting apoptosis. Moreover, PGG reverses DOX-induced EMT by downregulating mesenchymal markers (vimentin and β-catenin) and upregulating epithelial markers (E-cadherin). Furthermore, it effectively inhibits STAT3 phosphorylation, associated with cell survival and migration. Conclusions: These results highlight the potential of PGG as an adjuvant therapy in TNBC treatment. PGG synergizes with DOX, which potentiates its anticancer effects while mitigating adverse reactions.
Collapse
Affiliation(s)
- Jiraporn Kantapan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.I.)
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Phattarawadee Innuan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.I.)
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sarawut Kongkarnka
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Padchanee Sangthong
- Division of Biochemistry and Biochemical Innovation, Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.I.)
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| |
Collapse
|
|
5
|
Padovano F, Villa C. The development of drug resistance in metastatic tumours under chemotherapy: An evolutionary perspective. J Theor Biol 2024; 595:111957. [PMID: 39369787 DOI: 10.1016/j.jtbi.2024.111957] [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: 07/02/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/08/2024]
Abstract
We present a mathematical model of the evolutionary dynamics of a metastatic tumour under chemotherapy, comprising non-local partial differential equations for the phenotype-structured cell populations in the primary tumour and its metastasis. These equations are coupled with a physiologically-based pharmacokinetic model of drug administration and distribution, implementing a realistic delivery schedule. The model is carefully calibrated from the literature, focusing on BRAF-mutated melanoma treated with Dabrafenib as a case study. By means of long-time asymptotic and global sensitivity analyses, as well as numerical simulations, we explore the impact of cell migration from the primary to the metastatic site, physiological aspects of the tumour tissues and drug dose on the development of chemoresistance and treatment efficacy. Our findings provide a possible explanation for empirical evidence indicating that chemotherapy may foster metastatic spread and that metastases may be less impacted by the chemotherapeutic agent.
Collapse
Affiliation(s)
- Federica Padovano
- Sorbonne Université, CNRS, Université de Paris, Laboratoire Jacques-Louis Lions UMR 7598, 4 place Jussieu, 75005 Paris, France.
| | - Chiara Villa
- Sorbonne Université, CNRS, Université de Paris, Inria, Laboratoire Jacques-Louis Lions UMR 7598, 4 place Jussieu, 75005 Paris, France.
| |
Collapse
|
|
6
|
Luty M, Szydlak R, Pabijan J, Zemła J, Oevreeide IH, Prot VE, Stokke BT, Lekka M, Zapotoczny B. Tubulin-Targeted Therapy in Melanoma Increases the Cell Migration Potential by Activation of the Actomyosin Cytoskeleton─An In Vitro Study. ACS Biomater Sci Eng 2024; 10:7155-7166. [PMID: 39436192 PMCID: PMC11558564 DOI: 10.1021/acsbiomaterials.4c01226] [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: 07/03/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/23/2024]
Abstract
One of the most dangerous aspects of cancers is their ability to metastasize, which is the leading cause of death. Hence, it holds significance to develop therapies targeting the eradication of cancer cells in parallel, inhibiting metastases in cells surviving the applied therapy. Here, we focused on two melanoma cell lines─WM35 and WM266-4─representing the less and more invasive melanomas. We investigated the mechanisms of cellular processes regulating the activation of actomyosin as an effect of colchicine treatment. Additionally, we investigated the biophysical aspects of supplement therapy using Rho-associated protein kinase (ROCK) inhibitor (Y-27632) and myosin II inhibitor ((-)-blebbistatin), focusing on the microtubules and actin filaments. We analyzed their effect on the proliferation, migration, and invasiveness of melanoma cells, supported by studies on cytoskeletal architecture using confocal fluorescence microscopy and nanomechanics using atomic force microscopy (AFM) and microconstriction channels. Our results showed that colchicine inhibits the migration of most melanoma cells, while for a small cell population, it paradoxically increases their migration and invasiveness. These changes are also accompanied by the formation of stress fibers, compensating for the loss of microtubules. Simultaneous administration of selected agents led to the inhibition of this compensatory effect. Collectively, our results highlighted that colchicine led to actomyosin activation and increased the level of cancer cell invasiveness. We emphasized that a cellular pathway of Rho-ROCK-dependent actomyosin contraction is responsible for the increased invasive potential of melanoma cells in tubulin-targeted therapy.
Collapse
Affiliation(s)
- Marcin Luty
- Institute
of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | - Renata Szydlak
- Institute
of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | - Joanna Pabijan
- Institute
of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | - Joanna Zemła
- Institute
of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | - Ingrid H. Oevreeide
- Biophysics
and Medical Technology, Department of Physics, NTNU The Norwegian University of Science and Technology, Trondheim NO-7491, Norway
| | - Victorien E. Prot
- Biomechanics,
Department of Structural Engineering, NTNU
The Norwegian University of Science and Technology, Trondheim NO-7491, Norway
| | - Bjørn T. Stokke
- Biophysics
and Medical Technology, Department of Physics, NTNU The Norwegian University of Science and Technology, Trondheim NO-7491, Norway
| | - Malgorzata Lekka
- Institute
of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | | |
Collapse
|
|
7
|
Miyazaki K, Ariake K, Sato S, Miura T, Xun J, Douchi D, Ishida M, Ohtsuka H, Mizuma M, Nakagawa K, Kamei T, Unno M. GFPT2 expression is induced by gemcitabine administration and enhances invasion by activating the hexosamine biosynthetic pathway in pancreatic cancer. Clin Exp Metastasis 2024; 41:777-789. [PMID: 38888874 PMCID: PMC11499537 DOI: 10.1007/s10585-024-10298-y] [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: 02/09/2024] [Accepted: 06/05/2024] [Indexed: 06/20/2024]
Abstract
Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis.
Collapse
Affiliation(s)
- Kent Miyazaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kyohei Ariake
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Department of Gastroenterological Surgery, Sendai City Medical Center Sendai Open Hospital, Sendai, Japan.
| | - Satoko Sato
- Department of Pathology, Tohoku University Hospital, Sendai, Japan
| | - Takayuki Miura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jingyu Xun
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Daisuke Douchi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masaharu Ishida
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideo Ohtsuka
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Nakagawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| |
Collapse
|
|
8
|
Liu Z, Gao F, Min T, Shang Q, Wang B, Pu J. Individualized evaluation of risk and prognosis in uterine leiomyosarcoma patients with synchronous distant metastases: a real-world retrospective study. Front Oncol 2024; 14:1417226. [PMID: 39386189 PMCID: PMC11461169 DOI: 10.3389/fonc.2024.1417226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/26/2024] [Indexed: 10/12/2024] Open
Abstract
Background Uterine leiomyosarcoma (uLMS) accounts for roughly 70% of all uterine sarcomas, with recurrence and mortality rates notably higher than those of other uterine tumors. The prognosis of uLMS patients who have distant metastases remains poor. The objective of this study was to determine independent risk variables related to distant metastases in patients with uLMS and prognostic factors for those with distant metastases. Subsequently, two practical nomograms were developed and validated to assess the probability of distant metastases and predict survival outcomes for these with distant metastases, respectively. Methods A real-world retrospective study was carried out using data from patients diagnosed with primary uLMS in the Surveillance, Epidemiology, and End Results (SEER) database spanning the years 2010 to 2015. Univariate and multivariate logistic regression analyses were utilized to identify clinicopathological characteristics related to the risk of distant metastases, while univariate and multivariate Cox regressions were employed to determine prognostic factors. Then, a risk nomogram incorporating independent risk variables and a prognostic nomogram integrating independent prognostic factors were established in the training cohort and validated for accuracy in the validation cohort, respectively. Receiver operating characteristic (ROC) curves, area under the curve (AUC), and calibration curves were utilized to measure the accuracy of nomograms, while decision curve analysis (DCA) curves were employed to assess their clinical benefit capacity. Based on the median total point derived from the prognostic nomogram, patients were stratified into high- and low-risk groups. The differentiation ability of the prognostic nomogram was evaluated using Kaplan-Meier survival analysis with the log-rank test. Results The study encompassed 1,362 patients diagnosed with uLMS, among whom 337 cases (24.7%) manifested synchronous distant metastases at the initial diagnosis. Univariate and multivariate logistic regression analyses identified race, histological grade, T stage, N stage, tumor size, surgery, and chemotherapy as independent risk factors for distant metastases in uLMS patients. The outcomes of both univariate and multivariate Cox analyses indicated that surgery and chemotherapy emerged as independent protective factors for prognosis in uLMS patients with distant metastases, whereas higher histological grade and T stage were identified as independent risk factors. The risk nomogram incorporating independent risk variables and the prognostic nomogram integrating independent prognostic factors could respectively predict the risk of metastases and the prognosis very effectively in both training and validation cohorts. Conclusions In summary, we developed the novel well-validated risk nomogram to precisely assess the probability of metastases in uLMS patients and prognostic nomogram to predict the prognosis of those with distant metastases, providing decision-making guidance for tailoring individualized clinical management of these patients.
Collapse
Affiliation(s)
- Zhongli Liu
- Day Treatment Center, Mianyang Central Hospital, Mianyang, Sichuan, China
| | - Feng Gao
- Department of Medical Oncology, Mianyang Central Hospital, Mianyang, Sichuan, China
| | - Tao Min
- Day Treatment Center, Mianyang Central Hospital, Mianyang, Sichuan, China
| | - Qianqian Shang
- Department of Neurology, Mianyang Central Hospital, Mianyang, Sichuan, China
| | - Bin Wang
- Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jing Pu
- Department of Internal Medicine, Mianyang Central Hospital, Mianyang, Sichuan, China
| |
Collapse
|
|
9
|
Koc DC, Mănescu IB, Mănescu M, Dobreanu M. A Review of the Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Nonhematologic Malignancies. Diagnostics (Basel) 2024; 14:2057. [PMID: 39335736 PMCID: PMC11431542 DOI: 10.3390/diagnostics14182057] [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: 07/01/2024] [Revised: 09/09/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Biomarkers are crucial in cancer diagnostics, prognosis, and surveillance. Extensive research has been dedicated to identifying biomarkers that are broadly applicable across multiple cancer types and can be easily obtained from routine investigations such as blood cell counts. One such biomarker, the neutrophil-to-lymphocyte ratio (NLR), has been established as a prognostic marker in cancer. However, due to the dynamic nature of cancer diagnosis and treatment, periodic updates are necessary to keep abreast of the vast amount of published data. In this review, we searched the PubMed database and analyzed and synthesized recent literature (2018-February 2024) on the role of NLR in predicting clinical outcomes in nonhematologic malignancies. The search was conducted using the PubMed database. We included a total of 88 studies, encompassing 28,050 human subjects, and categorized the findings into four major groups: gastrointestinal cancer, cancers of the urinary tract and reproductive system, lung cancer, and breast cancer. Our analysis confirms that NLR is a reliable prognostic indicator in cancer, and we discuss the specific characteristics, limitations, and exceptions associated with its use. The review concludes with a concise Q&A section, presenting the most relevant take-home messages in response to five key practical questions on this topic.
Collapse
Affiliation(s)
- Defne Cigdem Koc
- Medical Campus Hamburg, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 11-15 Albert-Einstein-Ring, 22761 Hamburg, Germany; (D.C.K.); (I.B.M.)
| | - Ion Bogdan Mănescu
- Medical Campus Hamburg, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 11-15 Albert-Einstein-Ring, 22761 Hamburg, Germany; (D.C.K.); (I.B.M.)
- Department of Laboratory Medicine, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Gheorghe Marinescu, 540142 Targu Mures, Romania
| | - Măriuca Mănescu
- Department of Pediatrics, Emergency County Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu, 540136 Targu Mures, Romania
| | - Minodora Dobreanu
- Department of Laboratory Medicine, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Gheorghe Marinescu, 540142 Targu Mures, Romania
- Clinical Laboratory, Emergency County Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu, 540136 Targu Mures, Romania
| |
Collapse
|
|
10
|
Giles C, Lee J. Inflammation drives tumor growth in an immunocompetent implantable metastasis model. RESEARCH SQUARE 2024:rs.3.rs-4719290. [PMID: 39149496 PMCID: PMC11326373 DOI: 10.21203/rs.3.rs-4719290/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Nearly 90% of cancer deaths are due to metastasis. Conventional cancer therapeutics including chemotherapy, surgery, and radiotherapy, are effective in treating primary tumors, but may aggravate disseminated tumor cells (DTCs) into regaining a proliferative state. Models isolating the post dissemination environment are needed to address the potential risks of these therapies, however modeling post dissemination environments is challenging. Often, host organisms become moribund due to primary tumor mass before native metastatic niches can evolve. Implantable tissue engineered niches have been used to attract circulating tumor cells independent of the primary tumor. Here, we serially transplant such tissue engineered niches with recruited DTCs in order to isolate the post dissemination environment. After transplantaion, 69% of scaffolds developed overt post-dissemination cancer growth, however 100% of scaffolds did not grow to a life-threatening critical size within twelve weeks. Adjuvant chemotherapy, while initially effective, did not prevent long-term DTC growth in scaffolds. Subjecting these transplanted niches to surgical resection via biopsy punch enhanced CD31, MMP9, Ly6G, and tumor burden compared to control scaffolds. Biopsy punching was able to rescue tumor incidence from prior chemotherapy. This model of serial transplantation of engineered DTC niches is a highly controllable and flexible method of establishing and systematically investigating the post-dissemination niche.
Collapse
|
|
11
|
Sarkar M, Ma J, Tapadar S, Caggia S, Oyelere AK, Khan SA, Xie H. Development and validation of a sensitive LC-MS/MS assay of GT-14, a novel Gα i2 inhibitor, in rat plasma, and its application in pharmacokinetic study. J Pharm Biomed Anal 2024; 245:116183. [PMID: 38744031 PMCID: PMC11138141 DOI: 10.1016/j.jpba.2024.116183] [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: 02/23/2024] [Revised: 04/14/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
A sensitive and selective LC-MS/MS method was developed and validated for the quantitation of a novel Gαi2 inhibitor, GT-14, in rat plasma using a SCIEX 6500+ triple QUAD LC-MS system equipped with an ExionLC UHPLC unit. GT-14 (m/z 265.2 → 134.1) and griseofulvin (Internal Standard, IS) (m/z 353.1 → 285.1) were detected in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM). The assay was linear in the concentration range of 0.78-1000 ng/mL in rat plasma. Both accuracy and precision values were within the acceptance criteria of ±15 %, as established by FDA guidance. The matrix effect was negligible from plasma, with signal percentages of 98.5-106.9 %. The mean recovery was 104.5 %, indicating complete extraction of GT-14 from plasma. GT-14 was found to be stable under different experimental conditions. The validated method was successfully applied to evaluate plasma protein binding and in vivo pharmacokinetics of GT-14 in rats.
Collapse
Affiliation(s)
- Mahua Sarkar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Jing Ma
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Subhasish Tapadar
- School of Chemistry and Biochemistry, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 901 Atlantic Drive, Atlanta, GA 30318, USA
| | - Silvia Caggia
- Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr, Atlanta, GA 30314, USA
| | - Adegboyega K Oyelere
- School of Chemistry and Biochemistry, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 901 Atlantic Drive, Atlanta, GA 30318, USA
| | - Shafiq A Khan
- Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr, Atlanta, GA 30314, USA
| | - Huan Xie
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
| |
Collapse
|
|
12
|
Wills CA, Liu X, Chen L, Zhao Y, Liu Z, Spiegelman VS, Sundstrom J, Wang HG. Chemotherapy-induced small extracellular vesicles prime the pre-metastatic niche to accelerate neuroblastoma metastasis. Genes Dis 2024; 11:101017. [PMID: 38495925 PMCID: PMC10940767 DOI: 10.1016/j.gendis.2023.05.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/11/2023] [Accepted: 05/12/2023] [Indexed: 03/19/2024] Open
Affiliation(s)
- Carson A. Wills
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Xiaoming Liu
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Longgui Chen
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Yuanjun Zhao
- Department of Ophthalmology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Zhenqiu Liu
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Vladimir S. Spiegelman
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Jeffrey Sundstrom
- Department of Ophthalmology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Hong-Gang Wang
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| |
Collapse
|
|
13
|
Pécsi B, Mangel LC. The Real-Life Impact of Primary Tumor Resection of Synchronous Metastatic Colorectal Cancer-From a Clinical Oncologic Point of View. Cancers (Basel) 2024; 16:1460. [PMID: 38672540 PMCID: PMC11047864 DOI: 10.3390/cancers16081460] [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: 02/24/2024] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
AIM The complex medical care of synchronous metastatic colorectal (smCRC) patients requires prudent multidisciplinary planning and treatments due to various challenges caused by the primary tumor and its metastases. The role of primary tumor resection (PTR) is currently uncertain; strong arguments exist for and against it. We aimed to define its effect and find its best place in our therapeutic methodology. METHOD We performed retrospective data analysis to investigate the clinical course of 449 smCRC patients, considering treatment modalities and the location of the primary tumor and comparing the clinical results of the patients with or without PTR between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs. RESULTS A total of 63.5% of the 449 smCRC patients had PTR. Comparing their data to those whose primary tumor remained intact (IPT), we observed significant differences in median progression-free survival with first-line chemotherapy (mPFS1) (301 vs. 259 days; p < 0.0001; 1 y PFS 39.2% vs. 26.6%; OR 0.56 (95% CI 0.36-0.87)) and median overall survival (mOS) (760 vs. 495 days; p < 0.0001; 2 y OS 52.4 vs. 26.9%; OR 0.33 (95% CI 0.33-0.53)), respectively. However, in the PTR group, the average ECOG performance status was significantly better (0.98 vs. 1.1; p = 0.0456), and the use of molecularly targeted agents (MTA) (45.3 vs. 28.7%; p = 0.0005) and rate of metastasis ablation (MA) (21.8 vs. 1.2%; p < 0.0001) were also higher, which might explain the difference partially. Excluding the patients receiving MTA and MA from the comparison, the effect of PTR remained evident, as the mOS differences in the reduced PTR subgroup compared to the reduced IPT subgroup were still strongly significant (675 vs. 459 days; p = 0.0009; 2 y OS 45.9 vs. 24.1%; OR 0.37 (95% CI 0.18-0.79). Further subgroup analysis revealed that the site of the primary tumor also had a major impact on the outcome considering only the IPT patients; shorter mOS was observed in the extrapelvic IPT subgroup in contrast with the intrapelvic IPT group (422 vs. 584 days; p = 0.0026; 2 y OS 18.2 vs. 35.9%; OR 0.39 (95% CI 0.18-0.89)). Finally, as a remarkable finding, it should be emphasized that there were no differences in OS between the smCRC PTR subgroup and metachronous mCRC patients (mOS 760 vs. 710 days, p = 0.7504, 2 y OS OR 0.85 (95% CI 0.58-1.26)). CONCLUSIONS The role of PTR in smCRC is still not professionally justified. Our survey found that most patients had benefited from PTR. Nevertheless, further prospective trials are needed to clarify the optimal treatment sequence of smCRC patients and understand this cancer disease's inherent biology.
Collapse
Affiliation(s)
- Balázs Pécsi
- Institute of Oncotherapy, Clinical Center and Medical School, University of Pécs, 7624 Pécs, Hungary
| | | |
Collapse
|
|
14
|
Gayan S, Teli A, Sonawane A, Dey T. Impact of Chemotherapeutic Stress Depends on The Nature of Breast Cancer Spheroid and Induce Behavioral Plasticity to Resistant Population. Adv Biol (Weinh) 2024; 8:e2300271. [PMID: 38063815 DOI: 10.1002/adbi.202300271] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 11/20/2023] [Indexed: 04/15/2024]
Abstract
Cellular or tumor dormancy, identified recently as one of the main reasons behind post-therapy recurrence, can be caused by diverse reasons. Chemotherapy has recently been recognized as one of such reasons. However, in-depth studies of chemotherapy-induced dormancy are lacking due to the absence of an in vitro human-relevant model tailor-made for such a scenario. This report utilized multicellular breast cancer spheroid to create a primary platform for establishing a chemotherapy-induced dormancy model. It is observed that extreme chemotherapeutic stress affects invasive and non-invasive spheroids differently. Non-invasive spheroids exhibit more resilience and maintain viability and migrational ability, while invasive spheroids display heightened susceptibility and improved tumorigenic capacity. Heterogenous spheroids exhibit increased tumorigenic capacity while show minimal survival ability. Further probing of chemotherapeutically dormant spheroids is needed to understand the molecular mechanism and identify dormancy-related markers to achieve therapeutic success in the future.
Collapse
Affiliation(s)
- Sukanya Gayan
- Department of Biotechnology (merged with Institute of Bioinformatics and Biotechnology), Savitribai Phule Pune University, Pune, 411007, India
| | - Abhishek Teli
- Department of Biotechnology (merged with Institute of Bioinformatics and Biotechnology), Savitribai Phule Pune University, Pune, 411007, India
| | - Akshay Sonawane
- Department of Biotechnology (merged with Institute of Bioinformatics and Biotechnology), Savitribai Phule Pune University, Pune, 411007, India
| | - Tuli Dey
- Department of Biotechnology (merged with Institute of Bioinformatics and Biotechnology), Savitribai Phule Pune University, Pune, 411007, India
| |
Collapse
|
|
15
|
Huot JR, Livingston PD, Pin F, Thomas CR, Jamnick NA, Callaway CS, Bonetto A. Long-term Musculoskeletal Consequences of Chemotherapy in Pediatric Mice. FUNCTION 2024; 5:zqae011. [PMID: 38706958 PMCID: PMC11065107 DOI: 10.1093/function/zqae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/08/2024] [Accepted: 03/04/2024] [Indexed: 05/07/2024] Open
Abstract
Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 wk. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 wk after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 wk after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data support that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.
Collapse
Affiliation(s)
- Joshua R Huot
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
- Department of Kinesiology, School of Health and Human Sciences, Indiana University Purdue University Indianapolis, IN, 46202 USA
| | - Patrick D Livingston
- Department of Kinesiology, School of Health and Human Sciences, Indiana University Purdue University Indianapolis, IN, 46202 USA
| | - Fabrizio Pin
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
| | - Connor R Thomas
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202 USA
| | - Nicholas A Jamnick
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045 USA
| | - Chandler S Callaway
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045 USA
| | - Andrea Bonetto
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045 USA
- University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045 USA
| |
Collapse
|
|
16
|
Yoon H, Sabaté Del Río J, Cho SW, Park TE. Recent advances in micro-physiological systems for investigating tumor metastasis and organotropism. LAB ON A CHIP 2024; 24:1351-1366. [PMID: 38303676 DOI: 10.1039/d3lc01033c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Tumor metastasis involves complex processes that traditional 2D cultures and animal models struggle to fully replicate. Metastatic tumors undergo a multitude of transformations, including genetic diversification, adaptation to diverse microenvironments, and modified drug responses, contributing significantly to cancer-related mortality. Micro-physiological systems (MPS) technology emerges as a promising approach to emulate the metastatic process by integrating critical biochemical, biomechanical, and geometrical cues at a microscale. These systems are particularly advantageous simulating metastasis organotropism, the phenomenon where tumors exhibit a preference for metastasizing to particular organs. Organotropism is influenced by various factors, such as tumor cell characteristics, unique organ microenvironments, and organ-specific vascular conditions, all of which can be effectively examined using MPS. This review surveys the recent developments in MPS research from the past five years, with a specific focus on their applications in replicating tumor metastasis and organotropism. Furthermore, we discuss the current limitations in MPS-based studies of organotropism and propose strategies for more accurately replicating and analyzing the intricate aspects of organ-specific metastasis, which is pivotal in the development of targeted therapeutic approaches against metastatic cancers.
Collapse
Affiliation(s)
- Heejeong Yoon
- Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Jonathan Sabaté Del Río
- Center for Algorithmic and Robotized Synthesis (CARS), Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
| | - Seung Woo Cho
- Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Tae-Eun Park
- Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| |
Collapse
|
|
17
|
Bonni S, Brindley DN, Chamberlain MD, Daneshvar-Baghbadorani N, Freywald A, Hemmings DG, Hombach-Klonisch S, Klonisch T, Raouf A, Shemanko CS, Topolnitska D, Visser K, Vizeacoumar FJ, Wang E, Gibson SB. Breast Tumor Metastasis and Its Microenvironment: It Takes Both Seed and Soil to Grow a Tumor and Target It for Treatment. Cancers (Basel) 2024; 16:911. [PMID: 38473273 DOI: 10.3390/cancers16050911] [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: 01/09/2024] [Revised: 02/12/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Metastasis remains a major challenge in treating breast cancer. Breast tumors metastasize to organ-specific locations such as the brain, lungs, and bone, but why some organs are favored over others remains unclear. Breast tumors also show heterogeneity, plasticity, and distinct microenvironments. This contributes to treatment failure and relapse. The interaction of breast cancer cells with their metastatic microenvironment has led to the concept that primary breast cancer cells act as seeds, whereas the metastatic tissue microenvironment (TME) is the soil. Improving our understanding of this interaction could lead to better treatment strategies for metastatic breast cancer. Targeted treatments for different subtypes of breast cancers have improved overall patient survival, even with metastasis. However, these targeted treatments are based upon the biology of the primary tumor and often these patients' relapse, after therapy, with metastatic tumors. The advent of immunotherapy allowed the immune system to target metastatic tumors. Unfortunately, immunotherapy has not been as effective in metastatic breast cancer relative to other cancers with metastases, such as melanoma. This review will describe the heterogeneic nature of breast cancer cells and their microenvironments. The distinct properties of metastatic breast cancer cells and their microenvironments that allow interactions, especially in bone and brain metastasis, will also be described. Finally, we will review immunotherapy approaches to treat metastatic breast tumors and discuss future therapeutic approaches to improve treatments for metastatic breast cancer.
Collapse
Affiliation(s)
- Shirin Bonni
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB T2N 4N1, Canada
- The Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - M Dean Chamberlain
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada
- Saskatchewan Cancer Agency, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada
| | - Nima Daneshvar-Baghbadorani
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada
- Saskatchewan Cancer Agency, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada
| | - Andrew Freywald
- Department of Pathology, Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Denise G Hemmings
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T6G 2S2, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Sabine Hombach-Klonisch
- Department of Human Anatomy and Cell Science, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Thomas Klonisch
- Department of Human Anatomy and Cell Science, Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Afshin Raouf
- Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E OT5, Canada
- Cancer Care Manitoba Research Institute, Cancer Care Manitoba, Winnipeg, MB R3E OV9, Canada
| | - Carrie Simone Shemanko
- The Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Biological Sciences, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4, Canada
| | - Diana Topolnitska
- Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E OT5, Canada
- Cancer Care Manitoba Research Institute, Cancer Care Manitoba, Winnipeg, MB R3E OV9, Canada
| | - Kaitlyn Visser
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB T6G 2S2, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Franco J Vizeacoumar
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada
- Saskatchewan Cancer Agency, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada
| | - Edwin Wang
- Department of Biochemistry and Molecular Biology, Medical Genetics, and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Spencer B Gibson
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2R3, Canada
| |
Collapse
|
|
18
|
Peng X, Zheng J, Liu T, Zhou Z, Song C, Geng Y, Wang Z, Huang Y. Tumor Microenvironment Heterogeneity, Potential Therapeutic Avenues, and Emerging Therapies. Curr Cancer Drug Targets 2024; 24:288-307. [PMID: 37537777 DOI: 10.2174/1568009623666230712095021] [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: 04/17/2023] [Revised: 05/30/2023] [Accepted: 06/08/2023] [Indexed: 08/05/2023]
Abstract
OBJECTIVE This review describes the comprehensive portrait of tumor microenvironment (TME). Additionally, we provided a panoramic perspective on the transformation and functions of the diverse constituents in TME, and the underlying mechanisms of drug resistance, beginning with the immune cells and metabolic dynamics within TME. Lastly, we summarized the most auspicious potential therapeutic strategies. RESULTS TME is a unique realm crafted by malignant cells to withstand the onslaught of endogenous and exogenous therapies. Recent research has revealed many small-molecule immunotherapies exhibiting auspicious outcomes in preclinical investigations. Furthermore, some pro-immune mechanisms have emerged as a potential avenue. With the advent of nanosystems and precision targeting, targeted therapy has now transcended the "comfort zone" erected by cancer cells within TME. CONCLUSION The ceaseless metamorphosis of TME fosters the intransigent resilience and proliferation of tumors. However, existing therapies have yet to surmount the formidable obstacles posed by TME. Therefore, scientists should investigate potential avenues for therapeutic intervention and design innovative pharmacological and clinical technologies.
Collapse
Affiliation(s)
- Xintong Peng
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Jingfan Zheng
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Tianzi Liu
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Ziwen Zhou
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Chen Song
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Yan Geng
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Zichuan Wang
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Yan Huang
- Department of Oncology, Affiliated Hospital of Weifang Medical University, Weifang, China
| |
Collapse
|
|
19
|
Fu MX, Carvalho C, Milan-Chhatrisha B, Gadi N. Stereotactic Body Radiotherapy for Management of Pulmonary Oligometastases in Stage IV Colorectal Cancer: A Perspective. Clin Colorectal Cancer 2023; 22:402-410. [PMID: 37748936 DOI: 10.1016/j.clcc.2023.09.001] [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: 03/22/2022] [Revised: 02/05/2023] [Accepted: 09/05/2023] [Indexed: 09/27/2023]
Abstract
In pulmonary oligometastases from colorectal cancer (POM-CRC), metastasectomy is the primarily recommended treatment. Stereotactic body radiotherapy (SBRT) has been suggested as a viable alternative therapy. SBRT efficacy for POM-CRC is poorly delineated compared to selected non-CRC primaries. This perspective article aims to critically summarize the existing evidence regarding efficacy of SBRT in terms of overall survival (OS) and local control (LC), and factors modulating this, in the treatment of POM-CRC. Overall, reasonable LC and OS rates were observed. The wide range of expansions in planning target volume margins introduced variation in pretreatment protocols. Dose-fractionation schedules varied according to patient and tumor characteristics, though leverage of BED10 in select studies enabled standardization. An association between SBRT dose and improved OS and LC was observed across multiple studies. Prognostic factors that were associated with improved LC included: fewer oligometastases, absence of extra-pulmonary metastases, primary tumor histology, and smaller gross tumor volume. Differences in SBRT modality and techniques over time further confounded results. Many studies included patients receiving additional systemic therapies; preprotocol and adjuvant chemotherapies were identified as prognostic factors for LC. SBRT compared with metastasectomy showed no differences in short-term OS and LC outcomes. In conclusion, SBRT is an efficacious treatment for POM-CRC, in terms of OS and LC. Heterogeneity in study design, particularly pertaining to dose protocols, patient selection, and additional therapies should be controlled for future randomized studies to further validate SBRT efficacy.
Collapse
Affiliation(s)
- Michael X Fu
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.
| | - Catarina Carvalho
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Bella Milan-Chhatrisha
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Nishita Gadi
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| |
Collapse
|
|
20
|
Song KX, Wang JX, Huang D. Therapy-induced senescent tumor cells in cancer relapse. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:273-278. [PMID: 39036667 PMCID: PMC11256611 DOI: 10.1016/j.jncc.2023.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/08/2023] [Accepted: 09/14/2023] [Indexed: 07/23/2024] Open
Abstract
Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype (SASP). In an oncogenic context, senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease. However, recent studies have demonstrated that senescent tumor cells, which could spontaneously exist within cancer tissues or arise in response to various cancer interventions (the so-called therapy-induced senescence, TIS), can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse. This highlights the complex and multifaceted nature of cellular senescence in cancer biology. Here, we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse. We also discuss implications for future studies toward targeting these less appreciated cells.
Collapse
Affiliation(s)
- Ke-Xin Song
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jun-Xian Wang
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - De Huang
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
21
|
Sigdel I, Ofori-Kwafo A, Heizelman RJ, Nestor-Kalinoski A, Prabhakarpandian B, Tiwari AK, Tang Y. Biomimetic on-chip assay reveals the anti-metastatic potential of a novel thienopyrimidine compound in triple-negative breast cancer cell lines. Front Bioeng Biotechnol 2023; 11:1227119. [PMID: 37840664 PMCID: PMC10569307 DOI: 10.3389/fbioe.2023.1227119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/19/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction: This study presents a microfluidic tumor microenvironment (TME) model for evaluating the anti-metastatic efficacy of a novel thienopyrimidines analog with anti-cancer properties utilizing an existing commercial platform. The microfluidic device consists of a tissue compartment flanked by vascular channels, allowing for the co-culture of multiple cell types and providing a wide range of culturing conditions in one device. Methods: Human metastatic, drug-resistant triple-negative breast cancer (TNBC) cells (SUM159PTX) and primary human umbilical vein endothelial cells (HUVEC) were used to model the TME. A dynamic perfusion scheme was employed to facilitate EC physiological function and lumen formation. Results: The measured permeability of the EC barrier was comparable to observed microvessels permeability in vivo. The TNBC cells formed a 3D tumor, and co-culture with HUVEC negatively impacted EC barrier integrity. The microfluidic TME was then used to model the intravenous route of drug delivery. Paclitaxel (PTX) and a novel non-apoptotic agent TPH104c were introduced via the vascular channels and successfully reached the TNBC tumor, resulting in both time and concentration-dependent tumor growth inhibition. PTX treatment significantly reduced EC barrier integrity, highlighting the adverse effects of PTX on vascular ECs. TPH104c preserved EC barrier integrity and prevented TNBC intravasation. Discussion: In conclusion, this study demonstrates the potential of microfluidics for studying complex biological processes in a controlled environment and evaluating the efficacy and toxicity of chemotherapeutic agents in more physiologically relevant conditions. This model can be a valuable tool for screening potential anticancer drugs and developing personalized cancer treatment strategies.
Collapse
Affiliation(s)
- Indira Sigdel
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
| | - Awurama Ofori-Kwafo
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
| | - Robert J. Heizelman
- Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Andrea Nestor-Kalinoski
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, United States
| | | | - Amit K. Tiwari
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Yuan Tang
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
| |
Collapse
|
|
22
|
Wu M, Wu S, Chen Y, Sun L, Zhou J. Immune Activation Effects at Different Irradiated Sites and Optimal Timing of Radioimmunotherapy in Patients with Extensive-Stage Small Cell Lung Cancer: a Real-World Analysis. Biol Proced Online 2023; 25:24. [PMID: 37710179 PMCID: PMC10503112 DOI: 10.1186/s12575-023-00217-y] [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: 07/12/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023] Open
Abstract
BACKGROUND In view of the limited data on radiotherapy (RT) combined with immunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), this study aimed to identify the immune activation effect on different sites and the survival outcomes of radioimmunotherapy at different treatment stages. METHODS Forty-five patients diagnosed with ES-SCLC were included in this retrospective analysis. We collected the overall survival (OS) of the patients,, recorded the blood cell counts before, during, and after RT, and derived blood index ratios such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The datasets were analyzed using the Spearman rank correlation test, Kruskal-Wallis rank sum test and logistic regression. RESULTS Among the selected blood indices, the delta-NLR/PLR/Sll correlated with different irradiated organs, and the mean ranks of these three indices were the lowest in the brain-irradiated group during immunotherapy. Additionally, adjunct first-line immunotherapy with RT demonstrated a significant improvement compared to second- or third-line therapy and subsequent therapies. CONCLUSION Our findings suggest that compared to other organs, the strongest immune activation effect occurs with brain RT, and ES-SCLC patients who received radioimmunotherapy (RIT) earlier achieved higher OS rates.
Collapse
Affiliation(s)
- Min Wu
- Department of Radiation Oncology, Nanjing Medical University, Nanjing, Jiangsu, China
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shihao Wu
- Medical School, Anhui University of Science and Technology, Huainan, China
| | - Yuetong Chen
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Liangchao Sun
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
| | - Jundong Zhou
- Department of Radiation Oncology, Nanjing Medical University, Nanjing, Jiangsu, China.
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
| |
Collapse
|
|
23
|
Russo M, Panini N, Fabbrizio P, Formenti L, Becchetti R, Matteo C, Meroni M, Nastasi C, Cappelleri A, Frapolli R, Nardo G, Scanziani E, Ponzetta A, Bani MR, Ghilardi C, Giavazzi R. Chemotherapy-induced neutropenia elicits metastasis formation in mice by promoting proliferation of disseminated tumor cells. Oncoimmunology 2023; 12:2239035. [PMID: 37538353 PMCID: PMC10395252 DOI: 10.1080/2162402x.2023.2239035] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 08/05/2023] Open
Abstract
Chemotherapy is the standard of care for most malignancies. Its tumor debulking effect in adjuvant or neoadjuvant settings is unquestionable, although secondary effects have been reported that paradoxically promote metastasis. Chemotherapy affects the hematopoietic precursors leading to myelosuppression, with neutropenia being the main hematological toxicity induced by cytotoxic therapy. We used renal and lung murine tumor models metastatic to the lung to study chemotherapy-induced neutropenia (CIN) in the metastatic process. Cyclophosphamide and doxorubicin, two myelosuppressive drugs, but not cisplatin, increased the burden of artificial metastases to the lung, by reducing neutrophils. This effect was recapitulated by treatment with anti-Ly6G, the selective antibody-mediated neutrophil depletion that unleashed the formation of lung metastases in both artificial and spontaneous metastasis settings. The increased cancer dissemination was reversed by granulocyte-colony stimulating factor-mediated boosting of neutrophils in combination with chemotherapy. CIN affected the early metastatic colonization of the lung, quite likely promoting the proliferation of tumor cells extravasated into the lung at 24-72 hours. CIN did not affect the late events of the metastatic process, with established metastasis to the lung, nor was there any effect on the release of cancer cells from the primary, whose growth was, in fact, somewhat inhibited. This work suggests a role of neutrophils associated to a common cancer treatment side effect and claims a deep dive into the relationship between chemotherapy-induced neutropenia and metastasis.
Collapse
Affiliation(s)
- Massimo Russo
- Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Nicolò Panini
- Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Paola Fabbrizio
- Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Laura Formenti
- Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Riccardo Becchetti
- Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Cristina Matteo
- Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Marina Meroni
- Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Claudia Nastasi
- Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Andrea Cappelleri
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
- Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy
| | - Roberta Frapolli
- Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Giovanni Nardo
- Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Eugenio Scanziani
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
- Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy
| | - Andrea Ponzetta
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Maria Rosa Bani
- Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Carmen Ghilardi
- Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Raffaella Giavazzi
- Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| |
Collapse
|
|
24
|
Githaka JM, Pirayeshfard L, Goping IS. Cancer invasion and metastasis: Insights from murine pubertal mammary gland morphogenesis. Biochim Biophys Acta Gen Subj 2023; 1867:130375. [PMID: 37150225 DOI: 10.1016/j.bbagen.2023.130375] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/20/2023] [Accepted: 05/02/2023] [Indexed: 05/09/2023]
Abstract
Cancer invasion and metastasis accounts for the majority of cancer related mortality. A better understanding of the players that drive the aberrant invasion and migration of tumors cells will provide critical targets to inhibit metastasis. Postnatal pubertal mammary gland morphogenesis is characterized by highly proliferative, invasive, and migratory normal epithelial cells. Identifying the molecular regulators of pubertal gland development is a promising strategy since tumorigenesis and metastasis is postulated to be a consequence of aberrant reactivation of developmental stages. In this review, we summarize the pubertal morphogenesis regulators that are involved in cancer metastasis and revisit pubertal mammary gland transcriptome profiling to uncover both known and unknown metastasis genes. Our updated list of pubertal morphogenesis regulators shows that most are implicated in invasion and metastasis. This review highlights molecular linkages between development and metastasis and provides a guide for exploring novel metastatic drivers.
Collapse
Affiliation(s)
- John Maringa Githaka
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Leila Pirayeshfard
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Ing Swie Goping
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Department of Oncology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| |
Collapse
|
|
25
|
Akhunzianov AA, Nesterova AI, Wanrooij S, Filina YV, Rizvanov AA, Miftakhova RR. Unravelling the Therapeutic Potential of Antibiotics in Hypoxia in a Breast Cancer MCF-7 Cell Line Model. Int J Mol Sci 2023; 24:11540. [PMID: 37511298 PMCID: PMC10380719 DOI: 10.3390/ijms241411540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/04/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Antibiotics inhibit breast cancer stem cells (CSCs) by suppressing mitochondrial biogenesis. However, the effectiveness of antibiotics in clinical settings is inconsistent. This inconsistency raises the question of whether the tumor microenvironment, particularly hypoxia, plays a role in the response to antibiotics. Therefore, the goal of this study was to evaluate the effectiveness of five commonly used antibiotics for inhibiting CSCs under hypoxia using an MCF-7 cell line model. We assessed the number of CSCs through the mammosphere formation assay and aldehyde dehydrogenase (ALDH)-bright cell count. Additionally, we examined the impact of antibiotics on the mitochondrial stress response and membrane potential. Furthermore, we analyzed the levels of proteins associated with therapeutic resistance. There was no significant difference in the number of CSCs between cells cultured under normoxic and hypoxic conditions. However, hypoxia did affect the rate of CSC inhibition by antibiotics. Specifically, azithromycin was unable to inhibit sphere formation in hypoxia. Erythromycin and doxycycline did not reduce the ratio of ALDH-bright cells, despite decreasing the number of mammospheres. Furthermore, treatment with chloramphenicol, doxycycline, and tetracycline led to the overexpression of the breast cancer resistance protein. Our findings suggest that hypoxia may weaken the inhibitory effects of antibiotics on the breast cancer model.
Collapse
Affiliation(s)
- Almaz A Akhunzianov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Alfiya I Nesterova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Republican Clinical Oncology Dispensary Named after Prof. M.Z. Sigal, 420029 Kazan, Russia
| | - Sjoerd Wanrooij
- Department of Medical Biochemistry and Biophysics, Faculty of Medicine, Umeå University, 907 36 Umeå, Sweden
| | - Yulia V Filina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Regina R Miftakhova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| |
Collapse
|
|
26
|
Hartkopf AD, Fehm TN, Welslau M, Müller V, Schütz F, Fasching PA, Janni W, Witzel I, Thomssen C, Beierlein M, Belleville E, Untch M, Thill M, Tesch H, Ditsch N, Lux MP, Aktas B, Banys-Paluchowski M, Kolberg-Liedtke C, Wöckel A, Kolberg HC, Harbeck N, Stickeler E, Bartsch R, Schneeweiss A, Ettl J, Würstlein R, Krug D, Taran FA, Lüftner D. Update Breast Cancer 2023 Part 1 - Early Stage Breast Cancer. Geburtshilfe Frauenheilkd 2023; 83:653-663. [PMID: 37916183 PMCID: PMC10617391 DOI: 10.1055/a-2074-0551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 11/03/2023] Open
Abstract
With abemaciclib (monarchE study) and olaparib (OlympiA study) gaining approval in the adjuvant treatment setting, a significant change in the standard of care for patients with early stage breast cancer has been established for some time now. Accordingly, some diverse developments are slowly being transferred from the metastatic to the adjuvant treatment setting. Recently, there have also been positive reports of the NATALEE study. Other clinical studies are currently investigating substances that are already established in the metastatic setting. These include, for example, the DESTINY Breast05 study with trastuzumab deruxtecan and the SASCIA study with sacituzumab govitecan. In this review paper, we summarize and place in context the latest developments over the past months.
Collapse
Affiliation(s)
- Andreas D. Hartkopf
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Tanja N. Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | | | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Florian Schütz
- Gynäkologie und Geburtshilfe, Diakonissen-Stiftungs-Krankenhaus Speyer, Speyer, Germany
| | - Peter A. Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics; Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen-Nuremberg,
Erlangen, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Isabell Witzel
- Klinik für Gynäkologie, Universitätsspital Zürich, Zürich, Switzerland
| | - Christoph Thomssen
- Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Milena Beierlein
- Erlangen University Hospital, Department of Gynecology and Obstetrics; Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen-Nuremberg,
Erlangen, Germany
| | | | - Michael Untch
- Clinic for Gynecology and Obstetrics, Breast Cancer Center, Gynecologic Oncology Center, Helios Klinikum Berlin Buch, Berlin, Germany
| | - Marc Thill
- Department of Gynecology and Gynecological Oncology, Agaplesion Markus Krankenhaus, Frankfurt am Main, Germany
| | - Hans Tesch
- Oncology Practice at Bethanien Hospital, Frankfurt am Main, Germany
| | - Nina Ditsch
- Department of Gynecology and Obstetrics, University Hospital Augsburg, Augsburg, Germany
| | - Michael P. Lux
- Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten, St. Vincenz Krankenhaus GmbH, Paderborn, Germany
| | - Bahriye Aktas
- Department of Gynecology, University of Leipzig Medical Center, Leipzig, Germany
| | - Maggie Banys-Paluchowski
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | | | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | | | - Nadia Harbeck
- Breast Center, Department of Gynecology and Obstetrics and CCC Munich LMU, LMU University Hospital, München, Germany
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, Center for Integrated Oncology (CIO Aachen, Bonn, Cologne, Düsseldorf), University Hospital of RWTH Aachen, Aachen, Germany
| | - Rupert Bartsch
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Johannes Ettl
- Klinik für Frauenheilkunde und Gynäkologie, Klinikum Kempten, Klinikverbund Allgäu, Kempten, Germany
| | - Rachel Würstlein
- Breast Center, Department of Gynecology and Obstetrics and CCC Munich LMU, LMU University Hospital, München, Germany
| | - David Krug
- Klinik für Strahlentherapie, Universitätsklinkum Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Florin-Andrei Taran
- Department of Gynecology and Obstetrics, University Hospital Freiburg, Freiburg, Germany
| | - Diana Lüftner
- Medical University of Brandenburg Theodor-Fontane, Immanuel Hospital Märkische Schweiz, Buckow, Germany
| |
Collapse
|
|
27
|
Nam J, Schirmer AU, Loh C, Drewry DH, Macias E. Targeting the Divergent Roles of STK3 Inhibits Breast Cancer Cell Growth and Opposes Doxorubicin-Induced Cardiotoxicity In Vitro. Cancers (Basel) 2023; 15:2817. [PMID: 37345153 DOI: 10.3390/cancers15102817] [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: 03/18/2023] [Revised: 04/26/2023] [Accepted: 05/06/2023] [Indexed: 06/23/2023] Open
Abstract
Breast cancer (BCa) is the most prevalent type of cancer in women. Several therapies used in the treatment of breast cancer are associated with clinically important rates of cardiovascular toxicity during or after treatment exposure, including anthracyclines. There is a need for new BCa therapeutics and treatments that mitigate chemotherapy-induced cardiotoxicity in BCa. In this study, we examine the effects of Serine/Threonine Kinase 3 (STK3) inhibition in the context of BCa therapy and cardioprotection from doxorubicin. STK3 (also known as MST2) is a key member of the Hippo Tumor-Suppressor Pathway, which regulates cell growth and proliferation by inhibiting YAP/TAZ co-transcription factors. Canonically, STK3 should restrict BCa growth; however, we observed that STK3 is amplified in BCa and associated with worse patient outcomes, suggesting a noncanonical pro-tumorigenic role. We found BCa cell lines have varying dependence on STK3. SUM52PE cells had the highest expression and dependence on STK3 in genetic and pharmacological assays. MCF-7 and MDA-MB-231 were less sensitive to STK3 targeting in standard proliferation assays, but were STK3 dependent in colony formation and matrigel invasion assays. In contrast, STK3 inhibition mitigated the toxic effects of doxorubicin in H9C2 rat cardiomyocytes by increasing YAP expression. Importantly, STK3 inhibition in BCa cells did not interfere with the therapeutic effects of doxorubicin. Our studies highlight STK3 is a potential molecular target for BCa with dual therapeutic effects: suppression of BCa growth and progression, and chemoprotection in cardiomyocytes.
Collapse
Affiliation(s)
- Jiung Nam
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Amelia U Schirmer
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Chelsea Loh
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| | - David H Drewry
- Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Everardo Macias
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| |
Collapse
|
|
28
|
Lamouline A, Bersini S, Moretti M. In vitro models of breast cancer bone metastasis: analyzing drug resistance through the lens of the microenvironment. Front Oncol 2023; 13:1135401. [PMID: 37182144 PMCID: PMC10168004 DOI: 10.3389/fonc.2023.1135401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/27/2023] [Indexed: 05/16/2023] Open
Abstract
Even though breast cancers usually have a good outcome compared to other tumors, the cancer can progress and create metastases in different parts of the organism, the bone being a predilection locus. These metastases are usually the cause of death, as they are mostly resistant to treatments. This resistance can be caused by intrinsic properties of the tumor, such as its heterogeneity, but it can also be due to the protective role of the microenvironment. By activating signaling pathways protecting cancer cells when exposed to chemotherapy, contributing to their ability to reach dormancy, or even reducing the amount of drug able to reach the metastases, among other mechanisms, the specificities of the bone tissue are being investigated as important players of drug resistance. To this date, most mechanisms of this resistance are yet to be discovered, and many researchers are implementing in vitro models to study the interaction between the tumor cells and their microenvironment. Here, we will review what is known about breast cancer drug resistance in bone metastasis due to the microenvironment and we will use those observations to highlight which features in vitro models should include to properly recapitulate these biological aspects in vitro. We will also detail which elements advanced in vitro models should implement in order to better recapitulate in vivo physiopathology and drug resistance.
Collapse
Affiliation(s)
- Anaïs Lamouline
- Regenerative Medicine Technologies Laboratory, Laboratories for Translational Research (LRT), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
- Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Lugano, Switzerland
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy
| | - Simone Bersini
- Regenerative Medicine Technologies Laboratory, Laboratories for Translational Research (LRT), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
- Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Lugano, Switzerland
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Matteo Moretti
- Regenerative Medicine Technologies Laboratory, Laboratories for Translational Research (LRT), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
- Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Lugano, Switzerland
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
- Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
| |
Collapse
|
|
29
|
Joshi VB, Gutierrez Ruiz OL, Razidlo GL. The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights. Cancers (Basel) 2023; 15:cancers15072169. [PMID: 37046830 PMCID: PMC10093482 DOI: 10.3390/cancers15072169] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes.
Collapse
Affiliation(s)
- Vidhu B Joshi
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Omar L Gutierrez Ruiz
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Gina L Razidlo
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| |
Collapse
|
|
30
|
Zhu C, Liu P, Li C, Zhang Y, Yin J, Hou L, Zheng G, Liu X. Near-Death Cells Cause Chemotherapy-Induced Metastasis via ATF4-Mediated NF-κB Signaling Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205835. [PMID: 36739602 PMCID: PMC10074103 DOI: 10.1002/advs.202205835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/11/2023] [Indexed: 06/18/2023]
Abstract
Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify the mechanisms underlying chemotherapy-induced cancer recurrence and metastasis. It is revealed that a small subpopulation of "near-death cells" (NDCs) with compromised plasma membranes can reverse the death process to enhance survival and repopulation after exposure to lethal doses of cytotoxins. Moreover, these NDCs acquire enhanced tumorigenic and metastatic capabilities, but maintain chemosensitivity in multiple models. Mechanistically, cytotoxin exposure induces activating transcription factor 4 (ATF4)-dependent nonclassical NF-κB signaling activation; ultimately, this results in nuclear translocation of p52 and RelB in NDCs. Deletion of ATF4 in parental cancer cells significantly reduces colony formation and metastasis of NDCs, whereas overexpression of ATF4 activates the nonclassical NF-κB signaling pathway to promote chemotherapy-induced metastasis of NDCs. Overall, these results provide novel mechanistic insights into the chemotherapy-induced metastasis and indicate the pivotal role of NDCs in mediating tumor relapse after cytotoxic therapy. This study also suggests that targeting ATF4 may be an effective approach in improving the efficacy of chemotherapy.
Collapse
Affiliation(s)
- Chenchen Zhu
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Pei Liu
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Chuan‐Yuan Li
- Department of DermatologyDuke University Medical CenterDurhamNC27710USA
| | - Yuli Zhang
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Jiang Yin
- Cancer Research Institute and Cancer HospitalGuangzhou Medical UniversityGuangzhouGuangdong510180China
| | - Linlin Hou
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Guopei Zheng
- Cancer Research Institute and Cancer HospitalGuangzhou Medical UniversityGuangzhouGuangdong510180China
| | - Xinjian Liu
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
- Bebetter Med Inc.GuangzhouGuangdong510525China
| |
Collapse
|
|
31
|
Patras L, Shaashua L, Matei I, Lyden D. Immune determinants of the pre-metastatic niche. Cancer Cell 2023; 41:546-572. [PMID: 36917952 PMCID: PMC10170403 DOI: 10.1016/j.ccell.2023.02.018] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 03/16/2023]
Abstract
Primary tumors actively and specifically prime pre-metastatic niches (PMNs), the future sites of organotropic metastasis, preparing these distant microenvironments for disseminated tumor cell arrival. While initial studies of the PMN focused on extracellular matrix alterations and stromal reprogramming, it is increasingly clear that the far-reaching effects of tumors are in great part achieved through systemic and local PMN immunosuppression. Here, we discuss recent advances in our understanding of the tumor immune microenvironment and provide a comprehensive overview of the immune determinants of the PMN's spatiotemporal evolution. Moreover, we depict the PMN immune landscape, based on functional pre-clinical studies as well as mounting clinical evidence, and the dynamic, reciprocal crosstalk with systemic changes imposed by cancer progression. Finally, we outline emerging therapeutic approaches that alter the dynamics of the interactions driving PMN formation and reverse immunosuppression programs in the PMN ensuring early anti-tumor immune responses.
Collapse
Affiliation(s)
- Laura Patras
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Lee Shaashua
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Irina Matei
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| | - David Lyden
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| |
Collapse
|
|
32
|
Yang L, Haga Y, Nishimura A, Tsujii Y, Tanahashi S, Tsujino H, Higashisaka K, Tsutsumi Y. Fluorouracil exacerbates alpha-crystallin B chain-mediated cell migration in triple-negative breast cancer cell lines. Sci Rep 2023; 13:4010. [PMID: 36899050 PMCID: PMC10006185 DOI: 10.1038/s41598-023-31186-7] [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: 11/17/2022] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Among triple-negative breast cancer (TNBC) subtypes, the basal-like 2 (BL2) subtype shows the lowest survival rate and the highest risk of metastasis after treatment with chemotherapy. Research has shown that αB-crystallin (CRYAB) is more highly expressed in the basal-like subtypes than in the other subtypes and is associated with brain metastasis in TNBC patients. We therefore hypothesized that αB-crystallin is associated with increased cell motility in the BL2 subtype after treatment with chemotherapy. Here, we evaluated the effect of fluorouracil (5-FU), a typical chemotherapy for the treatment of TNBC, on cell motility by utilizing a cell line with high αB-crystallin expression (HCC1806). A wound healing assay revealed that 5-FU significantly increased cell motility in HCC1806 cells, but not in MDA-MB-231 cells, which have low αB-crystallin expression. Also, cell motility was not increased by 5-FU treatment in HCC1806 cells harboring stealth siRNA targeting CRYAB. In addition, the cell motility of MDA-MB-231 cells overexpressing αB-crystallin was significantly higher than that of MDA-MB-231 cells harboring a control vector. Thus, 5-FU increased cell motility in cell lines with high, but not low, αB-crystallin expression. These results suggest that 5-FU-induced cell migration is mediated by αB-crystallin in the BL2 subtype of TNBC.
Collapse
Affiliation(s)
- Lili Yang
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuya Haga
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Akihide Nishimura
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Tsujii
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Suzuno Tanahashi
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hirofumi Tsujino
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.,The Museum of Osaka University, 1-13 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Kazuma Higashisaka
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. .,Institute for Advanced Co-Creation Studies, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Yasuo Tsutsumi
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan. .,Global Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| |
Collapse
|
|
33
|
Saito S, Koya Y, Kajiyama H, Yamashita M, Nawa A. Indoxyl Sulfate Promotes Metastatic Characteristics of Ovarian Cancer Cells via Aryl Hydrocarbon Receptor-Mediated Downregulation of the Mas Receptor. J Transl Med 2023; 103:100025. [PMID: 36925201 DOI: 10.1016/j.labinv.2022.100025] [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: 01/20/2022] [Revised: 10/12/2022] [Accepted: 10/28/2022] [Indexed: 01/11/2023] Open
Abstract
Although platinum-combination chemotherapy shows a high response rate at the primary site, epithelial ovarian cancer (EOC) treatment remains challenging because of tumor recurrence and metastasis. Recent studies have revealed that chemotherapy paradoxically promotes cancer cell survival, proliferation, and metastasis, although the reason for this remains unclear. The underlying molecular mechanisms that contribute to chemotherapy-induced metastasis need to be elucidated to establish effective therapeutic strategies. Acute kidney injury is a known side effect of cisplatin treatment, and kidney dysfunction results in the accumulation of uremic toxins in the serum. The present study aimed to investigate whether indoxyl sulfate (IS), a representative uremic toxin, affects the pathophysiology of EOC. In this study, IS reduced the expression of Mas receptor (MasR) in cultured human EOC cells. Both knockdown of the aryl hydrocarbon receptor (AhR), which is an intracellular IS receptor, and inhibition of AhR function suppressed IS-mediated downregulation of MasR in SK-OV-3 cells. IS induced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an AhR-dependent manner. Inhibition of the STAT3 pathway or reactive oxygen species production suppressed the IS-mediated reduction of MasR. IS stimulated cell migration and invasion of SK-OV-3 cells in an AhR-dependent manner. Cisplatin-nephropathy model mice exhibited elevated levels of serum IS accompanied by elevated levels of blood urea nitrogen and serum creatinine. Furthermore, intraperitoneal administration of IS in mice promoted tumor growth and metastasis. Finally, we found that the MasR agonist Ang-(1-7) suppressed the IS-mediated effects on cell proliferation, migration, and invasion of SK-OV-3 cells. However, the knockdown of MasR expression by specific small interfering RNA in the absence of IS resulted in only minimal promotion of cell migration and invasion. These findings demonstrate that IS promotes malignancy in ovarian cancer via AhR-mediated downregulation of MasR function, whereas Ang-(1-7) attenuates this effect, thereby suggesting that Ang-(1-7) could provide a future treatment strategy for this cancer type.
Collapse
Affiliation(s)
- Shinichi Saito
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Japan; Bell Research Center for Reproductive Health and Cancer, Medical Corporation Kishokai, Nagoya, Aichi, Japan.
| | - Yoshihiro Koya
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Japan; Bell Research Center for Reproductive Health and Cancer, Medical Corporation Kishokai, Nagoya, Aichi, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan
| | - Mamoru Yamashita
- Bell Research Center for Reproductive Health and Cancer, Medical Corporation Kishokai, Nagoya, Aichi, Japan
| | - Akihiro Nawa
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Japan; Bell Research Center for Reproductive Health and Cancer, Medical Corporation Kishokai, Nagoya, Aichi, Japan
| |
Collapse
|
|
34
|
Tumor immunology. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00003-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
|
|
35
|
Luo K, Xu S, Zhao J, Liu F. Upregulation of lncRNA PINK1-AS Predicts the Distant Metastasis of Patients with Small Cell Lung Cancer. Mol Biotechnol 2023; 65:28-33. [PMID: 35764723 DOI: 10.1007/s12033-022-00512-1] [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: 12/08/2021] [Accepted: 05/11/2022] [Indexed: 01/22/2023]
Abstract
PINK1-AS has been shown to participate in gastric cancer, while its role in other tumors is unclear. This study was carried out to explore the participation of PINK1-AS in small cell lung cancer (SCLC). In this study, the expression of PINK1-AS in SCLC and paired non-cancer tissues from 60 SCLC patients and in plasma samples from 60 SCLC patients and 60 healthy controls was analyzed with RT-qPCR. Chi-squared t test was applied to analyze the associations between plasma expression levels of PINK1-AS and the clinical factors of the patients. Patients were followed up for 5 years to explore the role of PINK1-AS in the prognosis of SCLC. ROC curve analysis was applied to explore the role of PINK1-AS in the prediction of distant metastasis. Transwell assays were performed to evaluate the role of silencing and overexpression of PINK1-AS in the invasion and migration of SCLC cells. We found that PINK1-AS was upregulated in SCLC tissues compared to that in non-cancer tissues. Plasma expression levels of PINK1-AS were increased in SCLC patients compared to that in the controls. High plasma expression levels of PINK1-AS were closely associated with worse survival. Plasma expression of PINK1-AS was only closely correlated with distant tumor metastasis, but not other factors. High plasma expression levels of PINK1-AS effectively separated patients with distant metastasis from non-metastatic patients. Moreover, PINK1-AS positively regulated the migration and invasion of SCLC cells. Therefore, the upregulation of PINK1-AS predicts the distant metastasis of patients with SCLC.
Collapse
Affiliation(s)
- Kun Luo
- Department of Pulmonary and Critical Care Medicine, First Hospital of Qinhuangdao, No. 258 Wenhua Road, Haigang District, Qinhuangdao, 066000, Hebei, People's Republic of China
| | - Shufeng Xu
- Department of Pulmonary and Critical Care Medicine, First Hospital of Qinhuangdao, No. 258 Wenhua Road, Haigang District, Qinhuangdao, 066000, Hebei, People's Republic of China.
| | - Jing Zhao
- Department of Pulmonary and Critical Care Medicine, First Hospital of Qinhuangdao, No. 258 Wenhua Road, Haigang District, Qinhuangdao, 066000, Hebei, People's Republic of China
| | - Feifei Liu
- Department of Pulmonary and Critical Care Medicine, First Hospital of Qinhuangdao, No. 258 Wenhua Road, Haigang District, Qinhuangdao, 066000, Hebei, People's Republic of China
| |
Collapse
|
|
36
|
Entenberg D, Oktay MH, Condeelis JS. Intravital imaging to study cancer progression and metastasis. Nat Rev Cancer 2023; 23:25-42. [PMID: 36385560 PMCID: PMC9912378 DOI: 10.1038/s41568-022-00527-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2022] [Indexed: 11/17/2022]
Abstract
Navigation through the bulk tumour, entry into the blood vasculature, survival in the circulation, exit at distant sites and resumption of proliferation are all steps necessary for tumour cells to successfully metastasize. The ability of tumour cells to complete these steps is highly dependent on the timing and sequence of the interactions that these cells have with the tumour microenvironment (TME), including stromal cells, the extracellular matrix and soluble factors. The TME thus plays a major role in determining the overall metastatic phenotype of tumours. The complexity and cause-and-effect dynamics of the TME cannot currently be recapitulated in vitro or inferred from studies of fixed tissue, and are best studied in vivo, in real time and at single-cell resolution. Intravital imaging (IVI) offers these capabilities, and recent years have been a time of immense growth and innovation in the field. Here we review some of the recent advances in IVI of mammalian models of cancer and describe how IVI is being used to understand cancer progression and metastasis, and to develop novel treatments and therapies. We describe new techniques that allow access to a range of tissue and cancer types, novel fluorescent reporters and biosensors that allow fate mapping and the probing of functional and phenotypic states, and the clinical applications that have arisen from applying these techniques, reporters and biosensors to study cancer. We finish by presenting some of the challenges that remain in the field, how to address them and future perspectives.
Collapse
Affiliation(s)
- David Entenberg
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
| | - Maja H Oktay
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
| | - John S Condeelis
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Department of Cell Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
| |
Collapse
|
|
37
|
Przygodzka P, Soboska K, Sochacka E, Pacholczyk M, Braun M, Kassassir H, Papiewska-Pająk I, Kielbik M, Boncela J. Neuromedin U secreted by colorectal cancer cells promotes a tumour-supporting microenvironment. Cell Commun Signal 2022; 20:193. [PMID: 36482448 PMCID: PMC9733105 DOI: 10.1186/s12964-022-01003-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/04/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neuromedin U (NMU) was identified as one of the hub genes closely related to colorectal cancer (CRC) progression and was recently shown to be a motility inducer in CRC cells. Its autocrine signalling through specific receptors increases cancer cell migration and invasiveness. Because of insufficient knowledge concerning NMU accessibility and action in the tumour microenvironment, its role in CRC remains poorly understood and its potential as a therapeutic target is still difficult to define. METHODS NMU expression in CRC tissue was detected by IHC. Data from The Cancer Genome Atlas were used to analyse gene expression in CRC. mRNA and protein expression was detected by real-time PCR, immunoblotting or immunofluorescence staining and analysed using confocal microscopy or flow cytometry. Proteome Profiler was used to detect changes in the profiles of cytokines released by cells constituting tumour microenvironment after NMU treatment. NMU receptor activity was monitored by detecting ERK1/2 activation. Transwell cell migration, wound healing assay and microtube formation assay were used to evaluate the effects of NMU on the migration of cancer cells, human macrophages and endothelial cells. RESULTS Our current study showed increased NMU levels in human CRC when compared to normal adjacent tissue. We detected a correlation between high NMUR1 expression and shorter overall survival of patients with CRC. We identified NMUR1 expression on macrophages, endothelial cells, platelets, and NMUR1 presence in platelet microparticles. We confirmed ERK1/2 activation by treatment of macrophages and endothelial cells with NMU, which induced pro-metastatic phenotypes of analysed cells and changed their secretome. Finally, we showed that NMU-stimulated macrophages increased the migratory potential of CRC cells. CONCLUSIONS We propose that NMU is involved in the modulation and promotion of the pro-metastatic tumour microenvironment in CRC through the activation of cancer cells and other tumour niche cells, macrophages and endothelial cells. Video abstract.
Collapse
Affiliation(s)
- Patrycja Przygodzka
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Kamila Soboska
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland ,grid.10789.370000 0000 9730 2769Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Ewelina Sochacka
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland ,grid.10789.370000 0000 9730 2769Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Marcin Pacholczyk
- grid.6979.10000 0001 2335 3149Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland
| | - Marcin Braun
- grid.8267.b0000 0001 2165 3025Department of Pathology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Hassan Kassassir
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Izabela Papiewska-Pająk
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Michal Kielbik
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Joanna Boncela
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| |
Collapse
|
|
38
|
Cang W, Wu A, Gu L, Wang W, Tian Q, Zheng Z, Qiu L. Erastin enhances metastatic potential of ferroptosis-resistant ovarian cancer cells by M2 polarization through STAT3/IL-8 axis. Int Immunopharmacol 2022; 113:109422. [PMID: 36410184 DOI: 10.1016/j.intimp.2022.109422] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/25/2022] [Accepted: 10/31/2022] [Indexed: 11/19/2022]
Abstract
Erastin is a small molecule identified in chemical screen that is capable of inducing ferropotosis. There is collective evidence proving that erastin-induced ferroptosis exhibits anti-tumor potential within diverse caners, such as ovarian cancer (OC). However, most OC cells show relative resistance to ferroptosis induced by erastin. M2-polarized tumor-associated macrophages (TAMs) have an important effect on the OC tumor microenvironment (TME), which makes M2 polarization a noticeable part in the context of OC therapy. The immunomodulatory effects of erastin on ferroptosis-resistant OC cells remain poorly understood. Here, we found that low concentration of erastin greatly promoted ferroptosis-resistant OC cell invasion and migration via STAT3-mediated M2 polarization of macrophages. As revealed by in-vitro experimental results, erastin significantly increased metastases of ferroptosis-resistant OC, and the percentage of M2 macrophage infiltration was also raised after erastin treatment. Furthermore, erastin augmented IL-8 production of macrophages, and pharmacological blockage of IL-8 partially abrogated the stimulatory effect of erastin on ferroptosis-resistant OC cells. This study demonstrates a new mechanism undering the tumor-promoting activity of erastin and has implications for the STAT3/IL-8 axis as a potential target for ferroptosis-resistant OC cells to improve overall anti-tumor efficacy.
Collapse
Affiliation(s)
- Wei Cang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China
| | - Anyue Wu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China
| | - Liying Gu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China
| | - Wenjing Wang
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China
| | - Qi Tian
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China
| | - Zhong Zheng
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Lihua Qiu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, China.
| |
Collapse
|
|
39
|
Ye C, Qin S, Qiu S, Zhao L, Miao J, Chen Y, Zhou T. A lncRNA-immune checkpoint-related gene signature predicts metastasis-free survival in prostate adenocarcinoma. Transl Androl Urol 2022; 11:1691-1705. [PMID: 36632155 PMCID: PMC9827409 DOI: 10.21037/tau-22-711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 11/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background The 5-year overall survival rate in metastatic prostate adenocarcinoma (PRAD) is extremely low. Genomic studies of PRAD have improved our understanding of disease biology. However, the role of immune checkpoint genes (ICGs) in PRAD remains unclear. Methods Univariate and multivariate analyses were used to analyze genes associated with metastasis-free survival (MFS) in The Cancer Genome Atlas (TCGA)-PRAD dataset. The expressions of ADORA2A and TNFRSF18 were detected via immunohistochemical assay and real-time fluorescence quantitative PCR (RT-PCR) assay in our in-house cohort. The expression of long non-coding RNAs (lncRNAs) AL139287.1, SLC9A3-AS1, and SNHG12 were detected via RT-PCR assay in our in-house cohort. Stepwise regression, Cox regression, and nomogram analyses were used to evaluate the prognostic role of these genes in both the TCGA dataset and in-house cohort. The "pRRophetic" R package was used to evaluate drug sensitivity in the TCGA cohort according to the gene mRNA expression level. Results In our study, univariate and multivariate analyses revealed that the mRNA expressions of two ICGs, ADORA2A and TNFRSF18, were independent factors affecting MFS in PRAD patients. A prognostic 2-ICG model predicted the MFS of PRAD patients with medium-to-high accuracy in the TCGA dataset and in-house cohort. The expressions of AL139287.1, SLC9A3-AS1, and SNHG12 were correlated with ADORA2A and TNFRSF18. A prognostic lncRNA-ICG model predicted the MFS of PRAD patients with medium-to-high accuracy in the TCGA dataset and in-house cohort. In addition, correlation analyses between the sensitivity of doxorubicin, erlotinib, gemcitabine, or vinorelbine and AL139287.1, SLC9A3-AS1, SNHG12, ADORA2A, and TNFRSF18 were conducted. Conclusions Our results provide new targets for predicting tumor metastasis in PRAD and treating patients with metastatic PRAD.
Collapse
Affiliation(s)
- Chen Ye
- Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Shengfei Qin
- Department of Urology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shuang Qiu
- Department of Nuclear Medicine, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Lin Zhao
- Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jiaying Miao
- Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yuangui Chen
- Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Tie Zhou
- Department of Urology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| |
Collapse
|
|
40
|
Famta P, Shah S, Jain N, Shahrukh S, Bala Singh S, Srivastava S. Strategic combinatorial delivery of Tranilast and Paclitaxel using differently functionalized PLGA Nanoparticles for Enhanced penetration and Accumulation in Breast Tumor. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
41
|
Alexandrova A, Lomakina M. How does plasticity of migration help tumor cells to avoid treatment: Cytoskeletal regulators and potential markers. Front Pharmacol 2022; 13:962652. [PMID: 36278174 PMCID: PMC9582651 DOI: 10.3389/fphar.2022.962652] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor shrinkage as a result of antitumor therapy is not the only and sufficient indicator of treatment success. Cancer progression leads to dissemination of tumor cells and formation of metastases - secondary tumor lesions in distant organs. Metastasis is associated with acquisition of mobile phenotype by tumor cells as a result of epithelial-to-mesenchymal transition and further cell migration based on cytoskeleton reorganization. The main mechanisms of individual cell migration are either mesenchymal, which depends on the activity of small GTPase Rac, actin polymerization, formation of adhesions with extracellular matrix and activity of proteolytic enzymes or amoeboid, which is based on the increase in intracellular pressure caused by the enhancement of actin cortex contractility regulated by Rho-ROCK-MLCKII pathway, and does not depend on the formation of adhesive structures with the matrix, nor on the activity of proteases. The ability of tumor cells to switch from one motility mode to another depending on cell context and environmental conditions, termed migratory plasticity, contributes to the efficiency of dissemination and often allows the cells to avoid the applied treatment. The search for new therapeutic targets among cytoskeletal proteins offers an opportunity to directly influence cell migration. For successful treatment it is important to assess the likelihood of migratory plasticity in a particular tumor. Therefore, the search for specific markers that can indicate a high probability of migratory plasticity is very important.
Collapse
|
|
42
|
Monteran L, Ershaid N, Doron H, Zait Y, Scharff Y, Ben-Yosef S, Avivi C, Barshack I, Sonnenblick A, Erez N. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer. Nat Commun 2022; 13:5797. [PMID: 36184683 PMCID: PMC9527249 DOI: 10.1038/s41467-022-33598-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 09/23/2022] [Indexed: 12/02/2022] Open
Abstract
Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis. Complement signaling derived from cancer-associated fibroblasts (CAFs) mediates the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviates immune dysregulation and attenuates lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use. Accumulating evidence suggest that chemotherapy could paradoxically promote cancer metastasis. Here the authors report that, in preclinical breast cancer models, adjuvant treatment with doxorubicin induces the formation of an immunosuppressive metastatic niche that promotes relapse but that can be reverted with pharmacological blockade of complement signaling.
Collapse
Affiliation(s)
- Lea Monteran
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nour Ershaid
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hila Doron
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Zait
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ye'ela Scharff
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shahar Ben-Yosef
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Camila Avivi
- Department of Pathology, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Iris Barshack
- Department of Pathology, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Neta Erez
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| |
Collapse
|
|
43
|
Assessment of MRI to estimate metastatic dissemination risk and prometastatic effects of chemotherapy. NPJ Breast Cancer 2022; 8:101. [PMID: 36056005 PMCID: PMC9440218 DOI: 10.1038/s41523-022-00463-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 07/11/2022] [Indexed: 11/10/2022] Open
Abstract
Metastatic dissemination in breast cancer is regulated by specialized intravasation sites called “tumor microenvironment of metastasis” (TMEM) doorways, composed of a tumor cell expressing the actin-regulatory protein Mena, a perivascular macrophage, and an endothelial cell, all in stable physical contact. High TMEM doorway number is associated with an increased risk of distant metastasis in human breast cancer and mouse models of breast carcinoma. Here, we developed a novel magnetic resonance imaging (MRI) methodology, called TMEM Activity-MRI, to detect TMEM-associated vascular openings that serve as the portal of entry for cancer cell intravasation and metastatic dissemination. We demonstrate that TMEM Activity-MRI correlates with primary tumor TMEM doorway counts in both breast cancer patients and mouse models, including MMTV-PyMT and patient-derived xenograft models. In addition, TMEM Activity-MRI is reduced in mouse models upon treatment with rebastinib, a specific and potent TMEM doorway inhibitor. TMEM Activity-MRI is an assay that specifically measures TMEM-associated vascular opening (TAVO) events in the tumor microenvironment, and as such, can be utilized in mechanistic studies investigating molecular pathways of cancer cell dissemination and metastasis. Finally, we demonstrate that TMEM Activity-MRI increases upon treatment with paclitaxel in mouse models, consistent with prior observations that chemotherapy enhances TMEM doorway assembly and activity in human breast cancer. Our findings suggest that TMEM Activity-MRI is a promising precision medicine tool for localized breast cancer that could be used as a non-invasive test to determine metastatic risk and serve as an intermediate pharmacodynamic biomarker to monitor therapeutic response to agents that block TMEM doorway-mediated dissemination.
Collapse
|
|
44
|
Guarin JR, Fatherree JP, Oudin MJ. Chemotherapy treatment induces pro-invasive changes in liver ECM composition. Matrix Biol 2022; 112:20-38. [PMID: 35940338 PMCID: PMC10690958 DOI: 10.1016/j.matbio.2022.08.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 07/08/2022] [Accepted: 08/04/2022] [Indexed: 10/16/2022]
Abstract
Metastasis accounts for 90% of cancer-related deaths, yet the mechanisms by which cancer cells colonize secondary organs remain poorly understood. For breast cancer patients, metastasis to the liver is associated with poor prognosis and a median survival of 6 months. Standard of care is chemotherapy, but recurrence occurs in 30% of patients. Systemic chemotherapy has been shown to induce hepatotoxicity and fibrosis, but how chemotherapy impacts the composition of the liver extracellular matrix (ECM) remains unknown. Individual ECM proteins drive tumor cell proliferation and invasion, features that are essential for metastatic outgrowth in the liver. First, we find that the ECM of livers isolated from chemotherapy-treated MMTV-PyMT mice increases the invasion, but not proliferation, of metastatic breast cancer cells. Proteomic analysis of the liver ECM identified Collagen V to be more abundant in paclitaxel-treated livers. We show that Collagen V increases cancer cell invasion via α1β1 integrins and MAPK signaling, while also increasing the alignment of Collagen I, which has been associated with increased invasion. Treatment with obtustatin, an inhibitor specific to α1β1 integrins, inhibits tumor cell invasion in decellularized ECM from paclitaxel-treated livers. Overall, we show chemotherapy treatment alters the liver microenvironment, priming it as a pro-metastatic niche for cancer metastasis.
Collapse
Affiliation(s)
- Justinne R Guarin
- Department of Biomedical Engineering, Tufts University, Room 134, 200 College Ave, Medford, MA 20155, United States
| | - Jackson P Fatherree
- Department of Biomedical Engineering, Tufts University, Room 134, 200 College Ave, Medford, MA 20155, United States
| | - Madeleine J Oudin
- Department of Biomedical Engineering, Tufts University, Room 134, 200 College Ave, Medford, MA 20155, United States.
| |
Collapse
|
|
45
|
Bylapudi B, Thakur S, Nihla A, Subash A, Arakeri G, Rao VU. The potential role of immunity in the development of early distant metastases in locoregionally treated oral squamous cell carcinoma. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
|
|
46
|
Yang Y, Sun W. Recent advances in redox-responsive nanoparticles for combined cancer therapy. NANOSCALE ADVANCES 2022; 4:3504-3516. [PMID: 36134355 PMCID: PMC9400520 DOI: 10.1039/d2na00222a] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/20/2022] [Indexed: 05/23/2023]
Abstract
The combination of multiple therapeutic modalities has attracted increasing attention as it can achieve better therapeutic effects through different treatment mechanisms. However, traditional small molecule agents are non-specific to the tumor tissue, which leads to off-target toxic effects for healthy tissues. To solve this problem, a number of stimuli-responsive nanoscale drug-delivery systems have been developed. Among these stimuli, a high concentration of reactive oxygen species (ROS) and glutathione (GSH) are characteristic of the tumor microenvironment (TME), which can distinguish it from normal tissue. In this review, we summarize the redox-responsive nanoparticles (NPs) reported in the past three years classified by different functional groups, including GSH-responsive disulfide, ditelluride, and multivalent metal ions, ROS-responsive thioketal, arylboronic ester, aminoacrylate, and bilirubin as well as GSH/ROS dual-responsive diselenide and dicarbonyl thioethers. The prospects and challenges of redox-responsive NPs are also discussed.
Collapse
Affiliation(s)
- Yanjun Yang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology Dalian 116024 China
| | - Wen Sun
- State Key Laboratory of Fine Chemicals, Dalian University of Technology Dalian 116024 China
- Ningbo Institute of Dalian University of Technology Ningbo 315016 China
| |
Collapse
|
|
47
|
Lagou MK, Anastasiadou DP, Karagiannis GS. A Proposed Link Between Acute Thymic Involution and Late Adverse Effects of Chemotherapy. Front Immunol 2022; 13:933547. [PMID: 35844592 PMCID: PMC9283860 DOI: 10.3389/fimmu.2022.933547] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Epidemiologic data suggest that cancer survivors tend to develop a protuberant number of adverse late effects, including second primary malignancies (SPM), as a result of cytotoxic chemotherapy. Besides the genotoxic potential of these drugs that directly inflict mutational burden on genomic DNA, the precise mechanisms contributing to SPM development are poorly understood. Cancer is nowadays perceived as a complex process that goes beyond the concept of genetic disease and includes tumor cell interactions with complex stromal and immune cell microenvironments. The cancer immunoediting theory offers an explanation for the development of nascent neoplastic cells. Briefly, the theory suggests that newly emerging tumor cells are mostly eliminated by an effective tissue immunosurveillance, but certain tumor variants may occasionally escape innate and adaptive mechanisms of immunological destruction, entering an equilibrium phase, where immunologic tumor cell death "equals" new tumor cell birth. Subsequent microenvironmental pressures and accumulation of helpful mutations in certain variants may lead to escape from the equilibrium phase, and eventually cause an overt neoplasm. Cancer immunoediting functions as a dedicated sentinel under the auspice of a highly competent immune system. This perspective offers the fresh insight that chemotherapy-induced thymic involution, which is characterized by the extensive obliteration of the sensitive thymic epithelial cell (TEC) compartment, can cause long-term defects in thymopoiesis and in establishment of diverse T cell receptor repertoires and peripheral T cell pools of cancer survivors. Such delayed recovery of T cell adaptive immunity may result in prolonged hijacking of the cancer immunoediting mechanisms, and lead to development of persistent and mortal infections, inflammatory disorders, organ-specific autoimmunity lesions, and SPMs. Acknowledging that chemotherapy-induced thymic involution is a potential risk factor for the emergence of SPM demarcates new avenues for the rationalized development of pharmacologic interventions to promote thymic regeneration in patients receiving cytoreductive chemotherapies.
Collapse
Affiliation(s)
- Maria K. Lagou
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
- Tumor Microenvironment and Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, United States
| | - Dimitra P. Anastasiadou
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
- Tumor Microenvironment and Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, United States
| | - George S. Karagiannis
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
- Tumor Microenvironment and Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, United States
- Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein Cancer Center, Bronx, NY, United States
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, United States
- Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, United States
| |
Collapse
|
|
48
|
Tumour invasion and dissemination. Biochem Soc Trans 2022; 50:1245-1257. [PMID: 35713387 PMCID: PMC9246329 DOI: 10.1042/bst20220452] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/16/2022] [Accepted: 05/30/2022] [Indexed: 11/17/2022]
Abstract
Activating invasion and metastasis are one of the primary hallmarks of cancer, the latter representing the leading cause of death in cancer patients. Whilst many advances in this area have been made in recent years, the process of cancer dissemination and the underlying mechanisms governing invasion are still poorly understood. Cancer cells exhibit multiple invasion strategies, including switching between modes of invasion and plasticity in response to therapies, surgical interventions and environmental stimuli. The ability of cancer cells to switch migratory modes and their inherent plasticity highlights the critical challenge preventing the successful design of cancer and anti-metastatic therapies. This mini-review presents current knowledge on the critical models of tumour invasion and dissemination. We also discuss the current issues surrounding current treatments and arising therapeutic opportunities. We propose that the establishment of novel approaches to study the key biological mechanisms underlying the metastatic cascade is critical in finding novel targets that could ultimately lead to complete inhibition of cancer cell invasion and dissemination.
Collapse
|
|
49
|
Yang Y, Zhang Y, Wang R, Rong X, Liu T, Xia X, Fan J, Sun W, Peng X. A glutathione activatable pro-drug-photosensitizer for combined chemotherapy and photodynamic therapy. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.03.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
50
|
Fineberg S, Tian X, Makower D, Harigopal M, Lo Y. EZH2 Protein Expression in Triple-negative Breast Cancer Treated With Neoadjuvant Chemotherapy: An Exploratory Study of Association With Tumor Response and Prognosis. Appl Immunohistochem Mol Morphol 2022; 30:157-164. [PMID: 35262520 DOI: 10.1097/pai.0000000000000998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/08/2021] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Neaodjuvant chemotherapy is used to treat high risk triple-negative breast cancer (TNBC). Residual cancer burden (RCB) is used to predict risk of relapse after neoadjuvant chemotherapy (NAC); however, it cannot predict disease recurrence with certainty. EZH2 is a targetable oncogenic protein overexpressed in TNBC and associated with metastasis and stem cell expansion. We quantified EZH2 protein expression in TNBC before NAC to examine potential utility as a predictive and prognostic biomarker. MATERIALS AND METHODS We retrospectively identified 63 patients with localized TNBC treated with NAC. We quantified EZH2 nuclear expression in pretherapy biopsies using a score which included intensity and percent of positive cells at each intensity. EZH2 expression was evaluated as a continuous variable and dichotomized at a score of 210. Logistic regression analysis was used to determine association between EZH2 expression and RCB, tumor-infiltrating lymphocytes, clinicopathologic features and disease-free survival. RESULTS There was no significant association between EZH2 score and posttreatment RCB class evaluated as a continuous variable (P=0.831) or dichotomized at 210 (P=0.546). On multivariable logistic regression, adjusted for covariates including RCB, EZH2 >210 was associated with development of metastasis (odds ratio=14.35, 95% confidence interval: 2.69-76.66; P=0.002). Logistic regression was run with EZH2 scores as a continuous variable and increased EZH2 score was associated with metastasis (odds ratio=1.10, 95% confidence interval: 1.00-1.03; P=0.047). CONCLUSION In our study of TNBC treated with NAC, high EZH2 expression in pretherapy core biopsies was significantly associated with metastatic recurrence independent of RCB. The potential value of EZH2 as a biomarker to improve stratification of outcome after NAC should be explored further.
Collapse
Affiliation(s)
| | | | | | - Malini Harigopal
- Department of Pathology, Yale University School of Medicine and Yale New Haven Hospital, New Haven, CT
| | - Yungtai Lo
- Departments of Pathology
- Epidemiology and Population Health Montefiore Medical Center and The Albert Einstein College of Medicine, Bronx, NY
| |
Collapse
|