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Carrasco-Díaz LM, Gallardo A, Voltà-Durán E, Virgili AC, Páez D, Villaverde A, Vazquez E, Álamo P, Unzueta U, Casanova I, Mangues R, Alba-Castellon L. A Targeted Nanotoxin Inhibits Colorectal Cancer Growth Through Local Tumor Pyroptosis and Eosinophil Infiltration and Degranulation. Int J Nanomedicine 2025; 20:2445-2460. [PMID: 40034221 PMCID: PMC11873025 DOI: 10.2147/ijn.s499192] [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: 10/03/2024] [Accepted: 01/14/2025] [Indexed: 03/05/2025] Open
Abstract
Background Colorectal cancer (CRC) has traditionally been treated with genotoxic chemotherapy to activate pro-apoptotic proteins to induce anticancer effects. However, cancer cells develop resistance to apoptosis, which leads to recurrence and poor prognosis. Moreover, this kind of therapy has been shown to be highly toxic to healthy tissues and, therefore, to patients. To overcome this issue, we developed a self-assembly tumor-targeted nanoparticle, T22-DITOX-H6, that incorporates the T22 peptide (a CXCR4 ligand) to selectively target cells overexpressing CXCR4, fused to the catalytic domain of diphtheria toxin, that exhibits a potent cytotoxic effect on these CXCR4+ cancer cells that exhibits potent cytotoxic effects on CXCR4-overexpressing cancer cells through the activation of pyroptosis, an immunogenic type of cell death. Methods Colorectal CXCR4-expressing tumor cells (CT26-CXCR4+) were implanted subcutaneously into immunocompetent mice to study the effects of T22-DITOX-H6 treatment on tumor growth, cell death and innate immune cell recruitment to the tumor. Results Here, we demonstrated that the T22-DITOX-H6 nanoparticle selectively activated pyroptosis, an immunogenic cell death that differs from apoptosis, leading to cell death in CXCR4-expressing cells, without affecting the viability of CXCR4-lacking cells. In addition, the nanoparticle administered to tumor-bearing mice induced a local antitumor effect due to the selective activation of pyroptosis in CXCR4+ targeted cancer cells. Biochemical analysis of plasma and histological analysis of non-tumor tissues revealed no differences between the groups. Remarkably, pyroptosis activation stimulates eosinophil infiltration into the tumor microenvironment, an effect recently reported to have an anti-tumorigenic function. Conclusion These results highlight the dual role of CXCR4-targeted cytotoxic nanoparticle in eliminating cancer cells and boosting the self-immune response without compromising healthy organs.
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Affiliation(s)
- Luis Miguel Carrasco-Díaz
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Alberto Gallardo
- Department of Pathology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - Eric Voltà-Durán
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Anna C Virgili
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - David Páez
- Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
- CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Antonio Villaverde
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Esther Vazquez
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Patricia Álamo
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Ugutz Unzueta
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Isolda Casanova
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Ramon Mangues
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Lorena Alba-Castellon
- Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain
- Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
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Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
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Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
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Toh JWT, Ferguson AL, Spring KJ, Mahajan H, Palendira U. Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status. World J Clin Oncol 2021; 12:238-248. [PMID: 33959477 PMCID: PMC8085513 DOI: 10.5306/wjco.v12.i4.238] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC).
AIM To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status.
METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry (IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera (Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in inForm 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.
RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ TRM cells in the MSI (BRAF mutant and wild type) group over the microsatellite stable (MSS) group. There was a statistically significant difference in CD8+ TRM between high level MSI (MSI-H):BRAF mutant [22.57, 95% confidence interval (CI): 14.31-30.84] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0076 andMSI-H:BRAF wild type [16.18 (95%CI: 10.44-21.93)] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells (both CD8+CD103- and CD8+CD103+TRM) between MSI-H: BRAF mutant and wild type CRC.
CONCLUSION This study has shown that CD8+ TRM are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ TRM may play a role in the immunogenicity in MSI-H CRC (BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of TRM cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.
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Affiliation(s)
- James Wei Tatt Toh
- Division of Surgery and Anaesthesia, Department of Colorectal Surgery, Westmead Hospital, Westmead Clinical School, The University of Sydney, Ingham Institute for Applied Medical Research, Westmead 2145, NSW, Australia
| | - Angela L Ferguson
- Department of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, Human Viral & Cancer Immunology, Centenary Institute, Charles Perkin Centre, The University of Sydney, Sydney 2000, NSW, Australia
| | - Kevin J Spring
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool Hospital, Liverpool Clinical School, University of Western Sydney, South Western Clinical School UNSW, Liverpool 2170, NSW, Australia
| | - Hema Mahajan
- Department of Anatomical Pathology, ICPMR, Westmead Hospital, Westmead 2145, NSW, Australia
| | - Umaimainthan Palendira
- Department of Immunology and Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney 2000, NSW, Australia
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Hand F, Ryan EJ, Harrington C, Durand M, Maguire D, O'Farrelly C, Hoti E, Geoghegan JG. Chemotherapy and repeat resection abrogate the prognostic value of neutrophil lymphocyte ratio in colorectal liver metastases. HPB (Oxford) 2020; 22:670-676. [PMID: 31570259 DOI: 10.1016/j.hpb.2019.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 08/30/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Evolution in surgical and oncological management of CRLM has called into question the utility of clinical risk scores. We sought to establish if neutrophil lymphocyte ratio (NLR) has a prognostic role in this patient cohort. METHODS From 2005 to 2015,379 hepatectomies were performed for CRLM, 322 underwent index hepatectomy, 57 s hepatectomies were performed. Clinicopathological data were obtained from a prospectively maintained database. Variables associated with longterm survival following index and second hepatectomy were identified by Cox regression analyses and reviewed along with 30-day post-operative morbidity and mortality. RESULTS Following index hepatectomy 1-,3-and 5-year survival was 90.7%, 68.1% and 48.6%. Major resection, positive margins and >5 tumours were negatively associated with survival. Those with elevated NLR(>5) had a median survival of 55 months, compared to 70 months with lower NLR(p = 0.027). Following neoadjuvant chemotherapy, no association between NLR and survival was demonstrated (p = 0.93). Furthermore, NLR >5 had no impact on prognosis following repeat hepatectomy. Tumour diameter >5 cm (p = 0.04) was the sole predictor of poorer survival (p = 0.049). CONCLUSION Despite elevated NLR correlating with shorter survival following index hepatectomy, this effect is negated by neoadjuvant chemotherapy and second hepatectomy for recurrent disease. This data would not support the use of NLR in the preoperative decision algorithm for patients with CRLM.
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Affiliation(s)
- Fiona Hand
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland; School of Biochemistry & Immunology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
| | - Elizabeth J Ryan
- Centre for Colorectal Disease, School of Medicine, University College Dublin and St. Vincent's Hospital, Elm Park, Dublin 4, Ireland
| | - Cuan Harrington
- Department of Surgical Affairs, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Michael Durand
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Donal Maguire
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry & Immunology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Emir Hoti
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Justin G Geoghegan
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor. Int J Mol Sci 2020; 21:ijms21061991. [PMID: 32183342 PMCID: PMC7139914 DOI: 10.3390/ijms21061991] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment. This review revises the current evidence, aiming to propose potential molecular targets and specific treatments for this aggressive tumor.
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Toh JWT, Lim SH, MacKenzie S, de Souza P, Bokey L, Chapuis P, Spring KJ. Association Between Microsatellite Instability Status and Peri-Operative Release of Circulating Tumour Cells in Colorectal Cancer. Cells 2020; 9:cells9020425. [PMID: 32059485 PMCID: PMC7072224 DOI: 10.3390/cells9020425] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 12/21/2022] Open
Abstract
Microsatellite instability (MSI) in colorectal cancer (CRC) is a marker of immunogenicity and is associated with an increased abundance of tumour infiltrating lymphocytes (TILs). In this subgroup of colorectal cancer, it is unknown if these characteristics translate into a measurable difference in circulating tumour cell (CTC) release into peripheral circulation. This is the first study to compare MSI status with the prevalence of circulating CTCs in the peri-operative colorectal surgery setting. For this purpose, 20 patients who underwent CRC surgery with curative intent were enrolled in the study, and peripheral venous blood was collected at pre- (t1), intra- (t2), immediately post-operative (t3), and 14–16 h post-operative (t4) time points. Of these, one patient was excluded due to insufficient blood sample. CTCs were isolated from 19 patients using the IsofluxTM system, and the data were analysed using the STATA statistical package. CTC number was presented as the mean values, and comparisons were made using the Student t-test. There was a trend toward increased CTC presence in the MSI-high (H) CRC group, but this was not statistically significant. In addition, a Poisson regression was performed adjusting for stage (I-IV). This demonstrated no significant difference between the two MSI groups for pre-operative time point t1. However, time points t2, t3, and t4 were associated with increased CTC presence for MSI-H CRCs. In conclusion, there was a trend toward increased CTC release pre-, intra-, and post-operatively in MSI-H CRCs, but this was only statistically significant intra-operatively. When adjusting for stage, MSI-H was associated with an increase in CTC numbers intra-operatively and post-operatively, but not pre-operatively.
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Affiliation(s)
- James W. T. Toh
- Medical Oncology, Ingham Institute of Applied Research, School of Medicine, Western Sydney University and SWS Clinical School, UNSW Sydney 2170, NSW, Australia
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Sydney 2145, Australia
- Department of Colorectal Surgery, Concord Hospital and Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney 2137, Australia
- Correspondence: (J.W.T.T.); (K.J.S.); Tel.: +61-2-8738-9032 (K.J.S.)
| | - Stephanie H. Lim
- Medical Oncology, Ingham Institute of Applied Research, School of Medicine, Western Sydney University and SWS Clinical School, UNSW Sydney 2170, NSW, Australia
| | - Scott MacKenzie
- Liverpool Clinical School, Western Sydney University, Sydney 2170, Australia
| | - Paul de Souza
- Medical Oncology, Ingham Institute of Applied Research, School of Medicine, Western Sydney University and SWS Clinical School, UNSW Sydney 2170, NSW, Australia
- Liverpool Clinical School, Western Sydney University, Sydney 2170, Australia
| | - Les Bokey
- Liverpool Clinical School, Western Sydney University, Sydney 2170, Australia
| | - Pierre Chapuis
- Department of Colorectal Surgery, Concord Hospital and Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney 2137, Australia
| | - Kevin J. Spring
- Medical Oncology, Ingham Institute of Applied Research, School of Medicine, Western Sydney University and SWS Clinical School, UNSW Sydney 2170, NSW, Australia
- Liverpool Clinical School, Western Sydney University, Sydney 2170, Australia
- Correspondence: (J.W.T.T.); (K.J.S.); Tel.: +61-2-8738-9032 (K.J.S.)
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Borroni EM, Qehajaj D, Farina FM, Yiu D, Bresalier RS, Chiriva-Internati M, Mirandola L, Štifter S, Laghi L, Grizzi F. Fusobacterium nucleatum and the Immune System in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2019; 15:149-156. [DOI: 10.1007/s11888-019-00442-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Trajkovski G, Ognjenovic L, Jota G, Hadzi-Manchev D, Trajkovska V, Volcevski G, Nikolova D, Petrushevska G, Janevska V, Janevski V. Tumour Lymphocytic Infiltration, Its Structure and Influence in Colorectal Cancer Progression. Open Access Maced J Med Sci 2018; 6:1003-1009. [PMID: 29983792 PMCID: PMC6026406 DOI: 10.3889/oamjms.2018.279] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/12/2018] [Accepted: 06/14/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND: The role of the immune system in the control of tumour progression has been stressed, recently. Many studies indicate the fact that the immune system can prevent tumour progression in several types of human malignant neoplasms including colorectal cancer. According to some authors, a higher density of “tumour-associated lymphocytes” (TAL), in malignant neoplasms, correlate with prolonged survival of patients. AIM: This study aims to determine the structure and the influence of the immune cells, TAL, in the progression of colorectal cancer (CRC). PATIENTS AND METHODS: The study included 103 patients with CRC operated at the University Clinic of Digestive Surgery in Skopje, whose operative material was analysed at the Institute of Pathology, Medical Faculty in Skopje. The structure of tumor-associated cells and their density were determined and were correlated with neoplasm’s grade, local growth (T), positive lymph nodes, lymphatic invasion and stage of the disease. RESULTS: CD4+, CD8+ and CD20+ lymphocytes (Ly) were found in TAL. The density of TAL was significantly different in neoplasms with different T status, lymphatic invasion, patients with and without nodal metastasis and patients with a different stage of the disease. The density of CD4+, CD8+, and CD20+ cells were significantly different in neoplasms with different T. The density of CD8+ and CD20+ lymphocytes was lower in patients with nodal metastasis and higher stage. CONCLUSION: The density of tumor-associated lymphocytes can anticipate the disease progression in patients with colorectal cancer, and the density of TAL influences the control of tumour progression.
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Affiliation(s)
- Gjorgji Trajkovski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Ljubomir Ognjenovic
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Gjorgji Jota
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Dragan Hadzi-Manchev
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Vanja Trajkovska
- University Clinic of TOARILUC, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Goce Volcevski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Dafina Nikolova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Gordana Petrushevska
- Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Vesna Janevska
- Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Vlado Janevski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
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Grizzi F, Basso G, Borroni EM, Cavalleri T, Bianchi P, Stifter S, Chiriva-Internati M, Malesci A, Laghi L. Evolving notions on immune response in colorectal cancer and their implications for biomarker development. Inflamm Res 2018; 67:375-389. [PMID: 29322204 DOI: 10.1007/s00011-017-1128-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Colorectal cancer (CRC) still represents the third most commonly diagnosed type of cancer in men and women worldwide. CRC is acknowledged as a heterogeneous disease that develops through a multi-step sequence of events driven by clonal selections; this observation is sustained by the fact that histologically similar tumors may have completely different outcomes, including a varied response to therapy. METHODS In "early" and "intermediate" stage of CRC (stages II and III, respectively) there is a compelling need for new biomarkers fit to assess the metastatic potential of their disease, selecting patients with aggressive disease that might benefit from adjuvant and targeted therapies. Therefore, we review the actual notions on immune response in colorectal cancer and their implications for biomarker development. RESULTS The recognition of the key role of immune cells in human cancer progression has recently drawn attention on the tumor immune microenvironment, as a source of new indicators of tumor outcome and response to therapy. Thus, beside consolidated histopathological biomarkers, immune endpoints are now emerging as potential biomarkers. CONCLUSIONS The introduction of immune signatures and cellular and molecular components of the immune system as biomarkers is particularly important considering the increasing use of immune-based cancer therapies as therapeutic strategies for cancer patients.
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Affiliation(s)
- Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
| | - Gianluca Basso
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Elena Monica Borroni
- Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Tommaso Cavalleri
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Paolo Bianchi
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Sanja Stifter
- Department of Pathology, School of Medicine, University of Rijeka, Rijeka, Croatia
| | | | - Alberto Malesci
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Hereditary Cancer Genetics Clinic, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Toh JWT, de Souza P, Lim SH, Singh P, Chua W, Ng W, Spring KJ. The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. Clin Colorectal Cancer 2016; 15:285-291. [PMID: 27553906 DOI: 10.1016/j.clcc.2016.07.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 07/09/2016] [Accepted: 07/12/2016] [Indexed: 12/17/2022]
Abstract
Colorectal cancers (CRCs) have been identified as potential targets for immunotherapy with programmed cell death (PD)-1 inhibitors. English-language publications from MedLine and Embase that evaluated PD-1/PD ligand 1 (PD-L1) in the CRC tumor microenvironment and clinical trials that assessed PD-1 inhibitors were included. Sixteen abstracts were screened. Fifteen met the inclusion criteria. After review of the full texts, this resulted in a final reference list of 8 studies eligible for review. Five studies that assessed PD-1/PD-L1 in CRC and 3 trials that assessed PD-1 inhibitors were included. PD-1-positive (PD-1+) tumor-infiltrating lymphocytes and PD-L1+ cancer cells featured more prominently in high-level microsatellite instability (MSI-H) CRCs compared with microsatellite stable (MSS) CRCs, except in 1 study in which PD-L1 expression was higher in MSS CRCs. In the 3 trials that assessed PD-1 inhibitor, all 3 studies recruited patients with metastatic CRC (mCRC). One study also included patients with recurrent CRC. The objective response according to the Response Evaluation Criteria in Solid Tumors criteria was 0% (19 CRC patients with unknown microsatellite instability status) in the nivolumab study. In the pembrolizumab study, the objective response to PD-1 inhibitor was 40% and 0% in patients with MSI-H and MSS mCRC, respectively (10 patients in the MSI-H group, 18 patients in the MSS group). Seventy-eight percent of the patients in the MSI-H mCRC group compared with 11% in the MSS mCRC group (P < .005) showed no further disease progression at 12 weeks. In the nivolumab with or without ipilimumab study, objective partial response at 12 weeks to PD-1 inhibitor with or without cytotoxic T-lymphocyte-associated protein 4 inhibitor was 25.5% to 33.3% and 5% in the MSI-H and MSS groups, respectively (100 patients in the MSI-H group, 20 patients in the MSS group). Clinical trials that assessed PD-1 inhibitor immunotherapy in patients with CRC have recruited only small cohorts of patients with mCRC. Studies on the tumor microenvironment have been on the basis of archival specimens with different antibody PD-1 and PD-L1 preparations for immunohistochemistry, independent from immunotherapy trials. Immunotherapy with PD-1 therapy has potential benefit for immunogenic MSI-H CRCs whereas there is no evidence to date to suggest immunotherapy benefit in MSS CRCs. The available data are limited, and there is no information on non-mCRCs. Future trials are under way to determine its benefits.
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Affiliation(s)
- James W T Toh
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Discipline of Surgery, Sydney Medical School, The University of Sydney, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Colorectal Surgery, Westmead Hospital, Westmead, New South Wales, Australia.
| | - Paul de Souza
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Stephanie H Lim
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
| | - Puneet Singh
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
| | - Wei Chua
- Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Weng Ng
- Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Kevin J Spring
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
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Tumor eosinophil infiltration and improved survival of colorectal cancer patients: Iowa Women's Health Study. Mod Pathol 2016; 29:516-27. [PMID: 26916075 PMCID: PMC4848192 DOI: 10.1038/modpathol.2016.42] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 01/16/2016] [Accepted: 01/18/2016] [Indexed: 02/08/2023]
Abstract
The role of the innate immune response in colorectal cancer is understudied. We examined the survival of colorectal cancer patients in relation to eosinophils, innate immune cells, infiltrating the tumor. Tissue microarrays were constructed from paraffin-embedded tumor tissues collected between 1986 and 2002 from 441 post-menopausal women diagnosed with colorectal cancer in the Iowa Women's Health Study. Tissue microarrays were stained with an eosinophil peroxidase antibody. Eosinophils in epithelial and stromal tissues within the tumor (called epithelial and stromal eosinophils, hereafter) were counted and scored into three and four categories, respectively. In addition, the degree of eosinophil degranulation (across epithelial and stromal tissues combined) was quantified and similarly categorized. We used Cox regression to estimate the hazard ratios and 95% confidence interval for all-cause and colorectal cancer death during 5-year follow-up after diagnosis and during follow-up through 2011 ('total follow-up'). The hazard ratios associated with eosinophil scores were adjusted for age of diagnosis, SEER (Surveillance, Epidemiology, and End Results) stage, tumor grade, body mass, and smoking history. High tumor stromal eosinophil score was inversely correlated with age and stage, and was associated with a decreased risk for all-cause and colorectal cancer death: hazard ratios (95% confidence intervals) were 0.61 (0.36-1.02; P-trend=0.02) and 0.48 (0.24-0.93; P-trend=0.01), respectively, during the 5-year follow-up for the highest vs lowest category. The inverse associations also existed for total follow-up for all-cause and colorectal cancer death for the highest vs lowest stromal eosinophil score: hazard ratios (95% confidence intervals) were 0.72 (0.48-1.08; P-trend=0.04) and 0.61 (0.34-1.12; P-trend=0.04), respectively. Further adjustment for treatment, comorbidities, additional lifestyle factors, tumor location, or molecular markers did not markedly change the associations, while adjustment for cytotoxic T cells slightly attenuated all associations. The infiltration of tumors with eosinophils, especially in stromal tissue, may be an important prognostic factor in colorectal cancer.
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Prakash H, Klug F, Nadella V, Mazumdar V, Schmitz-Winnenthal H, Umansky L. Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: lesson from insulinoma. Carcinogenesis 2016; 37:301-313. [PMID: 26785731 DOI: 10.1093/carcin/bgw007] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 01/12/2016] [Indexed: 01/01/2023] Open
Abstract
Tumor infiltrating iNOS+ macrophages under the influence of immunosuppressive tumor microenvironment gets polarized to tumor-promoting and immunosuppressive macrophages, known as tumor-associated macrophages (TAM). Their recruitment and increased density in the plethora of tumors has been associated with poor prognosis in cancer patients. Therefore, retuning of TAM to M1 phenotype would be a key for effective immunotherapy. Radiotherapy has been a potential non-invasive strategy to improve cancer immunotherapy and tumor immune rejection. Irradiation of late-stage tumor-bearing Rip1-Tag5 mice twice with 2 Gy dose resulted in profound changes in the inflammatory tumor micromilieu, characterized by induction of M1-associated effecter cytokines as well as reduction in protumorigenic and M2-associated effecter cytokines. Similarly, in vitro irradiation of macrophages with 2 Gy dose-induced expression of iNOS, NO, NFκBpp65, pSTAT3 and proinflammatory cytokines secretion while downregulating p38MAPK which are involved in iNOS translation and acquisition of an M1-like phenotype. Enhancement of various M2 effecter cytokines and angiogenic reprogramming in iNOs+ macrophage depleted tumors and their subsequent reduction by 2 Gy dose in Rip1-Tag5 transgenic mice furthermore demonstrated a critical role of peritumoral macrophages in the course of gamma irradiation mediated M1 retuning of insulinoma.
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Affiliation(s)
- Hridayesh Prakash
- Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany
| | - Felix Klug
- Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany
| | - Vinod Nadella
- School of Life Sciences , University of Hyderabad , Hyderabad 500046 , India
| | - Varadendra Mazumdar
- School of Life Sciences , University of Hyderabad , Hyderabad 500046 , India
| | | | - Liudmila Umansky
- Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany
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Changes of immunocytic phenotypes and functions from human colorectal adenomatous stage to cancerous stage: Update. Immunobiology 2015; 220:1186-96. [PMID: 26153874 DOI: 10.1016/j.imbio.2015.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 02/07/2023]
Abstract
It is believed that chronic inflammation as seen in patients with ulcerative colitis significantly increases the colorectal cancer (CRC) risk and functions as the main driving force for the development of colitis associated CRC. Recently, increasing evidences suggest that inflammation is also involved in the processing of sporadic CRCs that mostly develop from the preformed adenomas through a long-term progression. Within the adenoma/CRC tumor microenvironment, high dense immunocytes with significant phenotypic and functional changes have been observed. These cells might produce high level of inflammatory mediators and then affect the adenoma-cancer transition. In this review, we summarize the update on altered phenotypes and inflammatory mediators within the tumor microenvironment from the adenomatous stage to the cancerous stage, and discuss the significance of inflammatory mediators as biomarkers in predicating the progression from the premalignant adenoma lesion to the sporadic CRC lesion and the potential as therapeutic targets.
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Imai Y, Yamagishi H, Fukuda K, Ono Y, Inoue T, Ueda Y. Differential mucin phenotypes and their significance in a variation of colorectal carcinoma. World J Gastroenterol 2013; 19:3957-3968. [PMID: 23840140 PMCID: PMC3703182 DOI: 10.3748/wjg.v19.i25.3957] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 04/20/2013] [Accepted: 05/16/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate mucin expression profiles in colorectal carcinoma (CRC) histological subtypes with regard to clinicopathologic variables and prognosis. METHODS Mucin (MUC)2 and MUC5AC expressions were assessed by immunohistochemistry for a total of 250 CRC cases that underwent surgical resection. CRCs included 63 well-to-moderately differentiated adenocarcinomas (WMDAs), 91 poorly differentiated adenocarcinomas (PDAs), 81 mucinous adenocarcinoma (MUAs), and 15 signet-ring cell carcinomas (SRCCs). MUC2 and MUC5AC were scored as positive when ≥ 25% and ≥ 1% of cancer cells were stained positive, respectively. The human mutL homolog 1 and human mutS homolog 2 expressions were assessed by immunohistochemistry in PDAs to investigate mismatch-repair (MMR) status. Tumors that did not express either of these two were considered MMR-deficient. Results were analyzed for associations with clinicopathologic variables and the prognosis in individual histological CRC subtypes. RESULTS MUC2-positive and MUC5AC-positive WMDA percentages were 49.2% and 30.2%, respectively. In contrast, MUC2-positive and MUC5AC-positive PDA percentages were 9.5% and 51.6%, respectively. MUC2 levels tended to decrease and MUC5AC levels tended to increase from WMDA to PDA. In 21 tumors comprising both adenoma and adenocarcinoma components in a single tumor (4 WMDAs, 7 PDAs, and 10 MUAs), MUC2 was significantly downregulated in PDA and MUC5AC was downregulated in PDA and MUA in the adenoma-carcinoma sequence. These results suggested that MUC2 levels might be associated with malignant potential and that MUC5AC expression was an early event in tumorigenesis. Despite worse prognoses than WMDA, high MUC2 expression levels were maintained in MUA (95.1%) and SRCC (71.5%), which suggested a pathogenesis for these subtypes distinct from that of WMDA. No significant associations were found between MUC2 expression and any clinicopathologic variables in any histological subtype. MUC5AC expression in PDA was closely associated with right-sided location (P = 0.017), absence of nodal metastasis (P = 0.010), low tumor node metastasis stage (P = 0.010), and MMR deficiency (P = 0.003). MUC2 expression in WMDA was a marginal prognostic factor for recurrence/metastasis-free survival (RFS) by univariate Cox analysis (P = 0.077) but not by multivariate Cox analysis (P = 0.161). MUC5AC expression in PDA was a significant prognostic factor for RFS by univariate Cox analysis (P = 0.007) but not by multivariate Cox analysis (P = 0.104). Kaplan-Meier curves and log-rank tests revealed that MUC2 expression was marginally associated with a better WMDA prognosis [P = 0.064 for RFS and P = 0.172 for overall survival (OS)] but not for PDA. In contrast, MUC5AC expression was significantly and marginally associated with a better PDA prognosis in terms of RFS and OS, respectively (P = 0.004 for RFS and P = 0.100 for OS), but not for WMDA and MUA. CONCLUSION Mucin core protein expression profiles and clinical significance differ according to histological CRC subtypes. This may reflect different pathogeneses for these tumors.
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Samaka RM, Abd El-Wahed MM, Aiad HA, Kandil MA, Al-Sharaky DR. Does JC virus have a role in the etiology and prognosis of Egyptian colorectal carcinoma? APMIS 2012; 121:316-28. [PMID: 23030805 DOI: 10.1111/apm.12001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Accepted: 08/19/2012] [Indexed: 12/23/2022]
Abstract
John Cunningham virus (JCV) encodes an oncogenic T-antigen, which is capable of interacting with key growth regulatory pathways. JCV definite role as causal agent of human cancer, still awaits final confirmation. The present study was conducted to assess the possible role of JCV in Egyptian colorectal carcinoma (CRC) and correlate the expression with the clinicopathological features and survival. JCV in situ hybridization (ISH) signals and large T antigen immunoreactivity were examined in 87 colonic specimens. Positive glandular JCV ISH signals were detected in 20%, 25% and 40% of normal, adenoma and CRC cases respectively. Stromal JCV ISH signals were identified in 26% of CRC cases and 5% of adenoma however, normal mucosa did not show stromal positivity with significant difference (p = 0.03). Glandular JCV expression was significantly associated with high grade (p = 0.03), high mitotic index (p=0.02) and low apoptotic index (p = 0.00). Positive stromal signals were significantly associated with low apoptosis (p = 0.00). No positive nuclear immunostaining of JCV large T antigen was detected in all specimens. JCV stromal expression was the 2nd most powerful indicator of short survival and bad prognosis (p = 0.03) in CRC patients. JCV might play an etiological role in CRC tumorogenesis and short survival in Egyptian CRC patients.
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Affiliation(s)
- Rehab M Samaka
- Pathology Department, Menoufyia University, Shebin El-Kom, Egypt.
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16
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[Predictive value of intraepithelial (CD3) T-lymphocyte infiltration in resected colorectal cancer]. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:541-50. [PMID: 22858112 DOI: 10.1016/j.gastrohep.2012.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 05/05/2012] [Accepted: 05/09/2012] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) can induce an anti-tumoral immune response mediated by T-lymphocytes, which express CD3. OBJECTIVES To analyze the prognostic value of tissue expression of intraepithelial CD3 (CD3I) both overall and in the early tumoral stages. METHODS We revised 251 patients with resected CRC and favorable clinical course. CD3I expression was analyzed by immunohistochemistry. Multivariate analysis was used to analyze the variables independently associated with survival. We analyzed CD3I(+) expression in relation to survival and tumoral progression, both overall and in patients with pTNM(I-II) stage tumors. The sensitivity, specificity, positive and negative predictive values and diagnostic accuracy of CD3I expression were analyzed. RESULTS A total of 25.9% of patients with CRC were CD3I(+). After a mean follow-up of 74 months, CD3I(+) expression showed a favorable prognostic value for survival in the multivariate analysis (p=0.045). Survival curves and absence of tumoral progression were more favorable in CD3I(+) cases, both overall (p=0.009 and p=0.004, respectively), and in stages I-II (p=0.029 and p=0.015). The specificity and positive predictive value of CD3I(+) were as follows: Survival: overall: specificity =0.89; positive predictive value =0.91. Stage (I-II): specificity =0.94; positive predictive value =0.98. Absence of tumoral progression: overall: specificity=0.89; positive predictive value =0.88. Stage (I-II): specificity =0.92; positive predictive value =0.96. CONCLUSIONS CD3I expression has an favorable independent prognostic value, with statistically significantly higher percentages of survival and absence of tumoral progression. This more favorable outcome is maintained in the less advanced stages (I-II). CD3I expression shows high specificity and positive predictive value.
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Cui G, Shi Y, Cui J, Tang F, Florholmen J. Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets? Scand J Gastroenterol 2012; 47:367-77. [PMID: 22229663 DOI: 10.3109/00365521.2011.648950] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed.
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Affiliation(s)
- Guanglin Cui
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Deschoolmeester V, Baay M, Lardon F, Pauwels P, Peeters M. Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI. CANCER MICROENVIRONMENT 2011; 4:377-92. [PMID: 21618031 DOI: 10.1007/s12307-011-0068-5] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 05/19/2011] [Indexed: 12/14/2022]
Abstract
There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular anti-tumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.
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Affiliation(s)
- Vanessa Deschoolmeester
- Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium,
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Ohmori H, Luo Y, Kuniyasu H. Non-histone nuclear factor HMGB1 as a therapeutic target in colorectal cancer. Expert Opin Ther Targets 2011; 15:183-93. [DOI: 10.1517/14728222.2011.546785] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Motta JM, Nascimento CR, Rumjanek VM. Leukemic cell products down-regulate human dendritic cell differentiation. Cancer Immunol Immunother 2010; 59:1645-53. [PMID: 20607236 PMCID: PMC11031054 DOI: 10.1007/s00262-010-0890-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Accepted: 06/21/2010] [Indexed: 12/25/2022]
Abstract
The microenvironment produced by solid tumors is inhibitory to the immune system, inducing dendritic cell (DC) alterations, but there is a paucity of information regarding haematological malignances. The aim of this study was to investigate DC differentiation under the influence of leukemic cell products. Monocytes from healthy volunteers were cultured in the presence of IL-4 and GM-CSF for the generation of immature DCs. Supernatants from leukemic cultures were added to monocyte cultures during differentiation. The lineages used were K562, a chronic myeloid leukemia, HL-60, a promyelocytic leukemia and DAUDI, originated from Burkitt lymphoma. It was observed that the expression of CD14 remained high and the CD1a was low in the presence of tumor supernatants, while non-malignant supernatants did not affect these parameters. Furthermore, IL-1beta and TNF-alpha production by monocytes during differentiation was increased by the presence of tumor supernatants. The modifications on CD14 and CD1a expressions could be mimicked by the addition of exogenous IL-1beta and partially inhibited by the neutralization of IL-1beta. These results suggest that soluble products from leukemic cells interfere with DC differentiation and, in the present work, this effect could be mediated by monocyte-derived IL-1beta in response to tumor supernatants.
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Affiliation(s)
- Juliana Maria Motta
- Laboratório de Imunologia Tumoral, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco H2, Sala 003, Rio de Janeiro, 21941-590 Brazil
| | - Clarissa Rodrigues Nascimento
- Laboratório de Imunologia Tumoral, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco H2, Sala 003, Rio de Janeiro, 21941-590 Brazil
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vivian Mary Rumjanek
- Laboratório de Imunologia Tumoral, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco H2, Sala 003, Rio de Janeiro, 21941-590 Brazil
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Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 2010; 15:699-731. [PMID: 20584808 PMCID: PMC3228001 DOI: 10.1634/theoncologist.2010-0025] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 05/01/2010] [Indexed: 02/06/2023] Open
Abstract
Rapidly growing insights into the molecular biology of colorectal cancer (CRC) and recent developments in gene sequencing and molecular diagnostics have led to high expectations for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on molecular biomarkers are contradictory in their findings and the current reality is that no molecular marker, other than the KRAS gene in the case of epidermal growth factor receptor (EGFR)- targeted therapy for metastatic disease, has made it into clinical practice. Many markers investigated suffer from technical shortcomings, resulting from lack of quantitative techniques to capture the impact of the molecular alteration. This understanding has recently led to the more comprehensive approaches of global gene expression profiling or genome-wide analysis to determine prognostic and predictive signatures in tumors. In this review, an update of the most recent data on promising biological prognostic and/or predictive markers, including microsatellite instability, epidermal growth factor receptor, KRAS, BRAF, CpG island methylator phenotype, cytotoxic T lymphocytes, forkhead box P3-positive T cells, receptor for hyaluronic acid-mediated motility, phosphatase and tensin homolog, and T-cell originated protein kinase, in patients with CRC is provided.
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Affiliation(s)
- Vanessa Deschoolmeester
- Laboratory of Cancer Research and Clinical Oncology, Department of Medical Oncology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
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De Re V, Simula MP, Cannizzaro R, Pavan A, De Zorzi MA, Toffoli G, Canzonieri V. Galectin-10, eosinophils, and celiac disease. Ann N Y Acad Sci 2009; 1173:357-64. [PMID: 19758173 DOI: 10.1111/j.1749-6632.2009.04627.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Celiac disease (CD) is a chronic intestinal disease caused by intolerance to dietary wheat gluten in genetically susceptible individuals. There are a number of important open questions that impede the full explanation of the pathogenesis of this disease. We analyzed protein expression pattern in gut biopsies of CD subjects. Patients were selected and grouped according to histological inflammatory degree. Groups consisted of nine individuals with CD: three patients had a Marsh 0, three a Marsh I-II, and three a Marsh III. All CD patients showed a human leukocyte antigen DQ2/8 variant. Controls were three individuals with an excluded CD diagnosis. For the first time, galectin-10 expression was found related to the histological grade (P = 0.0092) and with the number of eosinophils in the lesion (P = 0.0040). Results suggest galectin-10 is a novel marker for evaluating CD tissue damage and eosinophils as a possible target for therapeutic approaches. Moreover, our data provide insights into alterations associated with CD tissue damage and pathogenesis.
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Affiliation(s)
- Valli De Re
- Experimental and Clinical Pharmacology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
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Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma. Br J Cancer 2009; 101:1393-401. [PMID: 19773754 PMCID: PMC2768440 DOI: 10.1038/sj.bjc.6605238] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. Methods: We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. Results: In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. Conclusions and interpretations: We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment.
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Moriwaki K, Noda K, Furukawa Y, Ohshima K, Uchiyama A, Nakagawa T, Taniguchi N, Daigo Y, Nakamura Y, Hayashi N, Miyoshi E. Deficiency of GMDS leads to escape from NK cell-mediated tumor surveillance through modulation of TRAIL signaling. Gastroenterology 2009; 137:188-198.e1982. [PMID: 19361506 DOI: 10.1053/j.gastro.2009.04.002] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2008] [Revised: 03/17/2009] [Accepted: 04/02/2009] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes apoptosis in cancer cells, but not normal cells, and is critically involved in tumor rejection through natural killer (NK) cell-mediated immune surveillance. Oligosaccharides are involved in various aspects in carcinogenesis, and fucosylation is one of the most important oligosaccharide modifications in cancer. Here, we report for the first time mutations of the GDP-mannose-4,6-dehydratase (GMDS) gene, which plays a pivotal role in fucosylation, in human colon cancer. The mutations resulted in resistance to TRAIL-induced apoptosis followed by escape from immune surveillance. METHODS The mock and GMDS-rescued HCT116 cells were investigated in terms of NK cell-mediated tumor surveillance by TRAIL signaling both in vitro and in vivo. The mutational analysis for GMDS was performed with kinds of cancer cell lines and tissues. RESULTS The mutation found here led to a virtually complete deficiency of cellular fucosylation, and transfection of the wild-type GMDS into HCT116 cells restored the cellular fucosylation. When mock and GMDS-rescued cells were transplanted into athymic mice, tumor growth and metastasis of the GMDS-rescued cells were dramatically suppressed through NK cell-mediated tumor surveillance. Furthermore, the GMDS-rescued cells showed high susceptibility to TRAIL-induced apoptosis, and anti-TRAIL blocking antibody suppressed the accelerated direct cell lysis of the GMDS-rescued cells by splenocytes. Similar mutations of the GMDS were found in certain human cancer tissues and other cell lines. CONCLUSIONS This pathway by GMDS mutation could be a novel type of cancer progression through cellular fucosylation and NK cell-mediated tumor surveillance.
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Affiliation(s)
- Kenta Moriwaki
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
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Djordjevic B, Hanna WM. Expression of c-kit in fibroepithelial lesions of the breast is a mast cell phenomenon. Mod Pathol 2008; 21:1238-45. [PMID: 18500266 DOI: 10.1038/modpathol.2008.78] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The expression of c-kit, a protooncogene tyrosine kinase receptor (CD117), in phyllodes tumors of the breast has been the subject of recent investigations. We examined stromal c-kit expression by immunohistochemistry in 68 cases comprising fibroadenomas, fibroadenomas with cellular stroma, and benign, borderline, and malignant phyllodes tumors. Membrane staining was identified in the epithelium of 82% of cases, representing all diagnostic categories in the study. Membrane and cytoplasmic staining was detected in scant cells in the stroma in 74% of the cases in the study, again, across all diagnostic entities. However, when toluidine blue and tryptase staining was performed, the staining pattern matched that of c-kit in the number of cells and their distribution, thereby confirming the presence of mast cells and excluding any appreciable level of true stromal c-kit staining. One borderline and one malignant phyllodes tumor showed a diffuse weak stromal signal, which could not be accounted for by toluidine blue and tryptase. These cases were further tested for the presence of known activating mutations of c-kit and PDGFR-alpha, and yielded negative results. Our findings indicate that c-kit is an unlikely player in the pathogenesis of fibroepithelial lesions of the breast. The positive stromal staining suggested previously by other authors may be attributed to mast cells. C-kit, therefore, has neither a diagnostic nor a prognostic role in phyllodes tumors, and there is no rationale for the treatment of recurrent of malignant phyllodes tumor patients with tyrosine kinase inhibitors.
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Affiliation(s)
- Bojana Djordjevic
- Department of Pathology, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, ON, Canada
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YUAN APING, STEIGEN SONJAE, GOLL RASMUS, VONEN BARTHOLD, HUSBEKK ANNE, CUI GUANGLIN, FLORHOLMEN JON. Dendritic cell infiltration pattern along the colorectal adenoma-carcinoma sequence. APMIS 2008; 18 Suppl 2:1-59. [DOI: 10.1111/j.1600-0463.2008.00879.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Abstract
Because chemotherapy is standard in the treatment of colorectal cancer, it is important to demonstrate whether immunizations may be given to patients receiving systemic chemotherapy. Although some studies have demonstrated immune responses in patients with metastatic colorectal carcinoma who failed standard chemotherapy, the setting of minimal residual disease may be the preferred setting for cancer vaccines. It may be important to choose antigens that have functions important to the cancer cell. The best adjuvant is not well established and may depend on the type of immune response desired. The immune system is "programmed" to down-regulate immune responses once they have become activated to avoid the development of autoimmune disease.
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González HD, Figueras J. Effect of surgical resection of metastatic disease on immune tolerance to cancer. How a systemic disease could be controlled by a local therapy. Clin Transl Oncol 2007; 9:571-7. [DOI: 10.1007/s12094-007-0105-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Bishara S, Griffin M, Cargill A, Bali A, Gore ME, Kaye SB, Shepherd JH, Van Trappen PO. Pre-treatment white blood cell subtypes as prognostic indicators in ovarian cancer. Eur J Obstet Gynecol Reprod Biol 2007; 138:71-5. [PMID: 17644243 DOI: 10.1016/j.ejogrb.2007.05.012] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2007] [Revised: 05/21/2007] [Accepted: 05/24/2007] [Indexed: 01/21/2023]
Abstract
OBJECTIVE Inflammatory cells can both suppress and stimulate tumour growth and their influence on clinical outcome in cancer patients has been studied in various cancer types. Here we have investigated their influence on outcome in primary epithelial ovarian cancer. STUDY DESIGN Serum white blood cell numbers according to subtype were recorded prior to treatment in 136 patients with primary epithelial ovarian cancer. Their correlation with overall survival and disease-free survival was analysed using both univariate and multivariate analysis adjusting for the known prognostic factors (age, stage and debulking status). RESULTS Multivariate analysis demonstrated that a lower lymphocyte fraction of total white blood cells was significantly associated with mortality (p<0.01). On univariate analysis (p=0.0027, HR=1.15), and multivariate analysis of those patients who were optimally debulked (p=0.036, HR=1.17), a higher monocyte count was significantly associated with recurrence. On multivariate analysis amongst those who were suboptimally debulked, a higher eosinophil count was predictive of both recurrence (p=0.0037, HR=1.77) and mortality (p=0.033, HR=1.73). CONCLUSION High monocyte counts amongst those who were optimally debulked independently predict adverse outcome in primary epithelial ovarian cancer.
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Affiliation(s)
- S Bishara
- Department of Gynaecological Oncology, Royal Marsden Hospital, London, UK.
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Jenkins JT, O'Neill G, Morran CG. The relationship between patient physiology and cancer-specific survival following curative resection of colorectal cancer. Br J Cancer 2007; 96:213-7. [PMID: 17242695 PMCID: PMC2359991 DOI: 10.1038/sj.bjc.6603560] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The impact of patient physiology on cancer-specific survival is poorly documented. Patient physiology predicted overall, cancer-specific (Physiology Score>30; HR 8.64 (95% CI 3.00-24.92); P=0.0005) and recurrence-free survival (Physiology Score >30; HR 7.44 (95% CI 1.99-27.73); P=0.003) independent of Dukes stage following potentially curative surgery for colorectal cancer. This independent negative association with survival is a novel observation.
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Affiliation(s)
- J T Jenkins
- Department of Surgery, Crosshouse Hospital, Kilmarnock, UK.
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Abstract
BACKGROUND Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. AIM To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. METHOD A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. RESULTS Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. CONCLUSIONS Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.
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Affiliation(s)
- C Evans
- Institution Colorectal Surgery Unit & Division of Oncology, St George's Hospital, Blackshaw Road, London, UK
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Kelly KA, Clemons PA, Yu AM, Weissleder R. High-throughput Identification of Phage-derived Imaging Agents. Mol Imaging 2006. [DOI: 10.2310/7290.2006.00003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Affiliation(s)
| | | | - Amy M. Yu
- Massachusetts General Hospital and Harvard Medical School, USA
| | - Ralph Weissleder
- Massachusetts General Hospital and Harvard Medical School, USA
- The Eli & Edythe Broad Institute of Harvard & MIT, USA
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Birgersdotter A, Sandberg R, Ernberg I. Gene expression perturbation in vitro--a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol 2005; 15:405-12. [PMID: 16055341 DOI: 10.1016/j.semcancer.2005.06.009] [Citation(s) in RCA: 425] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cells grown in vitro are dramatically perturbed by their new microenvironment. Analyses of genome-wide gene expression levels offer a first glance at which genes and pathways are affected in cell lines as compared to their tissues of origins. We have summarized available gene expression data and review how cell lines adapt to in vitro environments, to what degree they express markers of their tissues of origins and discuss how cells grown in three-dimensional (3D) cultures may have more physiological interactions with neighbouring cells and extracellular matrix. We will also discuss the interplay between malignant cells and stroma present in tumours but lacking in cell lines and how these differences might affect gene expression comparisons of cell lines to tumours. A model simulating impact of stromal cells on gene expression profiles is presented. Understanding the transcriptomes of cells grown in 2D and 3D cultures and how they compare to those of in vivo cells are important for improving cell line model systems and for the reconstituting of tissues in vitro.
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Affiliation(s)
- Anna Birgersdotter
- Microbiology and Tumor Biology Center, MTC, Karolinska Institutet, Box 280, 171 77 Stockholm, Sweden
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Wang QW, Lu HL, Song CC, Liu H, Xu CG. Radiosensitivity of human colon cancer cell enhanced by immunoliposomal docetaxel. World J Gastroenterol 2005; 11:4003-7. [PMID: 15996023 PMCID: PMC4502094 DOI: 10.3748/wjg.v11.i26.4003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To enhance the radiosensitivity of human colon cancer cells by docetaxel.
METHODS: Immunoliposomal docetaxel was prepared by coupling monoclonal antibody against carcinoembryonic antigen to cyanuric chloride at the PEG terminus of liposome. LoVo adenocarcinoma cell line was treated with immunoliposomal docetaxel or/and irradiation. MTT colorimetric assay was used to estimate cytotoxicity of immunoliposomal docetaxel and radiotoxicity. Cell cycle redistribution and apoptosis were determined with flow cytometry. Survivin expression in LoVo cells was verified by immunohistochemistry. D801 morphologic analysis system was used to semi-quantify immunohistochemical staining of survivin.
RESULTS: Cytotoxicity was induced by immunoliposomal docetaxel alone in a dose-dependent manner. Immunoli-posomal docetaxel yielded a cytotoxicity effect at a low dose of 2 nmol/L. With a single dose irradiation, the relative surviving fraction of LoVo cells showed a dose-dependent response, but there were no significant changes as radiation delivered from 4 to 8 Gy. Compared with liposomal docetaxel or single dose irradiation, strongly radiopotentiating effects of immunoliposomal docetaxel on LoVo cells were observed. A low dose of immunoliposomal docetaxel could yield sufficient radiosensitivity. Immunoliposomal docetaxel were achieved both specificity of the conjugated antibody and drug radiosensitization. Combined with radiation, immunoliposomal docetaxel significantly increased the percentage of G2/M cells and induced apoptosis, but significantly decreased the percentage of cells in G2/G1 and S phase by comparison with liposomal docetaxel. Immunohistochemical analysis showed that the brown stained survivin was mainly in cytoplasm of LoVo cells. Semi-quantitative analysis of the survivin immunostaining showed that the expression of survivin in LoVo cells under irradiation with immunoliposomal docetaxel was significantly decreased.
CONCLUSION: Immunoliposomal docetaxel is strongly effective for target radiosensitation in LoVo colon carcinoma cells, and may offer the potential to improve local radiotherapy.
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Affiliation(s)
- Qing-Wei Wang
- Cancer Research Center, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
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