Expression Profiling Using a cDNA Array and Immunohistochemistry for the Extracellular Matrix Genes FN-1, ITGA-3, ITGB-5, MMP-2, and MMP-9 in Colorectal Carcinoma Progression and Dissemination

Colorectal cancer dissemination depends on extracellular matrix genes related to remodeling and degradation of the matrix structure. This investigation intended to evaluate the association between FN-1, ITGA-3, ITGB-5, MMP-2, and MMP-9 gene and protein expression levels in tumor tissue with clinical and histopathological neoplastic parameters of cancer dissemination. The expression associations between ECM molecules and selected epithelial markers EGFR, VEGF, Bcl2, P53, and KI-67 have also been examined in 114 patients with colorectal cancer who underwent primary tumor resection. Quantitative real-time PCR and immunohistochemistry tissue microarray methods were performed in samples from the primary tumors. The gene expression results showed that the ITGA-3 and ITGB-5 genes were overexpressed in tumors with lymph node and distant metastasis (III/IV-stage tumors compared with I/II tumors). The MMP-2 gene showed significant overexpression in mucinous type tumors, and MMP-9 was overexpressed in villous adenocarcinoma histologic type tumors. The ECM genes MMP9 and ITGA-3 have shown a significant expression correlation with EGFR epithelial marker. The overexpression of the matrix extracellular genes ITGA-3 and ITGB-5 is associated with advanced stage tumors, and the genes MMP-2 and MMP-9 are overexpressed in mucinous and villous adenocarcinoma type tumors, respectively. The epithelial marker EGFR overactivity has been shown to be associated with the ECM genes MMP-9 and ITGA-3 expression.

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Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.2084 ◽

2006 ◽

Vol 24 (25) ◽

pp. 4069-4077 ◽

Cited By ~ 71

Author(s):

Neal J. Meropol ◽

Philip J. Gold ◽

Robert B. Diasio ◽

Michael Andria ◽

Mandeep Dhami ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Odds Ratio ◽

Thymidine Phosphorylase ◽

Dihydropyrimidine Dehydrogenase ◽

Predictive Marker ◽

Clinical Activity ◽

Primary Tumors ◽

Gene And Protein Expression ◽

Biomarker Analysis

Purpose To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity. Patients and Methods Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression. Results An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response. Conclusion These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.

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Proteomics analysis of the matrisome from MC38 experimental mouse liver metastases

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00014.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. G625-G639

Author(s):

Arseniy E. Yuzhalin ◽

Su Yin Lim ◽

Alex N. Gordon-Weeks ◽

Roman Fischer ◽

Benedikt M. Kessler ◽

...

Keyword(s):

Colorectal Cancer ◽

Extracellular Matrix ◽

Liver Metastases ◽

Cancer Cell ◽

Mouse Liver ◽

Hepatic Metastases ◽

Mass Spectrometry Analysis ◽

Annexin A1 ◽

Primary Tumors

Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble high-molecular-mass proteins maintaining tissue integrity and establishing cell–cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the ECM from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of proteins upregulated in the ECM significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the ECM component. One of the proteins upregulated in liver metastatic ECM, annexin A1, was not previously studied in the context of cancer-associated matrisome. Here, we show that annexin A1 was markedly upregulated in colon cancer cell lines compared with cancer cells of other origin and also over-represented in human primary colorectal lesions, as well as hepatic metastases, compared with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes annexin A1 as a putative target for this disease. NEW & NOTEWORTHY Here, the authors provide an extensive proteomics characterization of murine colorectal cancer liver metastasis matrisome (the ensemble of all extracellular matrix molecules). The findings presented in this study may enable identification of therapeutic targets or biomarkers of hepatic metastases.

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Primary tumor resection to improve survival in patients with metastatic colorectal cancer in the post-2000 era: A California Cancer Registry analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14570 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14570-e14570

Author(s):

Ana Milena Rodriguez Fahrni ◽

I-Yeh Gong ◽

Rosemary Cress ◽

Yingjia Chen ◽

Thomas John Semrad ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Metastatic Colorectal Cancer ◽

Cancer Registry ◽

Systemic Therapy ◽

Primary Tumor ◽

Tumor Resection ◽

Primary Tumor Resection ◽

Primary Tumors ◽

California Cancer Registry

e14570 Background: Resection of primary tumors in the setting of metastatic colorectal cancer (MCRC) is controversial. Fewer primary tumor resections are being performed due to the improved tumor responses and disease control rates associated with modern systemic therapy. Recent studies suggest a survival benefit for patients with MCRC who had primary tumors resection prior to systemic therapy. This analysis evaluates the independent prognostic impact of primary tumor resection on overall survival (OS) for patients with MCRC using the California Cancer Registry (CCR). Methods: We queried the CCR for all patients with MCRC diagnosed between 2003 and 2010. Patients were categorized by whether or not they had primary tumor resection at time of diagnosis. Covariates included gender, age, race/ethnicity, socioeconomic status (SES), and rural-urban commuting area (RUCA) score of patients. Univariate comparisons were made using the Kaplan Meier method. Multivariate comparisons were performed using the Cox proportional hazards regression method. Results: 19,836 patients met the criteria for analysis of whom 11,566 (58%) had primary tumor resection. Primary tumor resection rates declined over this time period (63% in 2003 v. 52.8% in 2010, p<0.0001), varied by SES (55% v. 62%: lowest versus highest, p<0.001) and residence (63% in rural versus 58% for urban, P=0.0160). On multivariate analysis, overall survival was significantly better for patients that had primary tumor resection (HR: 0.467 [95% CI: 0.467-0.482]; p<0.0001). Survival was statistically longer in younger patients (HR: 1.385 for age 65-75, HR: 2.217 if greater than age 75), highest SES (HR: 0.869, p<0.0001), Hispanics (HR: 0.884, p<0001), and Asian/Pacific Islanders (HR:0.892, p<0.0001). Overall survival was worse for African Africans (HR:1.105, P=0.0001). Conclusions: Our study demonstrates the independent prognostic value on survival of primary tumor resection in patients with MCRC. There is significant variability of resection rates by SES and rural-urban residence. As analysis of CCR data cannot eliminate the influence of patient and provider biases, a prospective randomized trial is warranted.

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Nuclear Factor Kappa B, Matrix Metalloproteinase-1, p53, and Ki-67 Expressions in the Primary Tumors and the Lymph Node Metastases of Colorectal Cancer Cases

Gastroenterology Research and Practice ◽

10.1155/2015/945392 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Ibrahim Meteoglu ◽

Ibrahim Halil Erdogdu ◽

Pars Tuncyurek ◽

Adil Coskun ◽

Nil Culhaci ◽

...

Keyword(s):

Colorectal Cancer ◽

Lymph Node ◽

Matrix Metalloproteinase ◽

Lymph Node Metastases ◽

Survival Rates ◽

Ki 67 ◽

Primary Tumors ◽

Metastatic Cells ◽

Matrix Metalloproteinase 1 ◽

Node Metastases

Colorectal cancer (CRC) is the third most frequent malignancy. Many factors such as NF-κB, matrix metalloproteinase-1 (MMP-1), p53, and Ki-67 are likely to be involved in its development and progression. Lymph node metastases indicate increased tumor burden and tumor cell heterogeneity and affect both the treatment strategies and the prognosis. In this study, expressions of NF-κB, MMP-1, p53, and Ki-67 were between the primary tumors and lymph node metastases in 110 Dukes’ stage C, CRC cases by immunohistochemical methods, related to patients’ clinical outcomes. NF-κB, p53, and Ki-67 expressions were significantly higher in the metastatic lymph nodes compared to the primary tumor tissues (P=0.04,P=0.04, andP=0.01, resp.). In the metastatic lymph nodes NF-κB expression was correlated with both p53 (r=0.546,P=0.003) and Ki-67 (r=0.586,P=0.0001) expressions. The univariant and multivariant analyses showed that only “pT stage” preserved an independent prognostic significance for recurrence-free survival rates and 5-year overall survival rates (P<0.001for both). Metastatic cells can acquire different biological characteristics compared to their primaries. Elucidation of properties acquired by metastatic cells is important in order to better determine prognosis, reverse drug resistance, and discover new treatment alternatives.

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Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial

Journal of Clinical Oncology ◽

10.1200/jco.20.02447 ◽

2021 ◽

Vol 39 (10) ◽

pp. 1098-1107

Author(s):

Yukihide Kanemitsu ◽

Kohei Shitara ◽

Junki Mizusawa ◽

Tetsuya Hamaguchi ◽

Dai Shida ◽

...

Keyword(s):

Colorectal Cancer ◽

Primary Tumor ◽

Tumor Resection ◽

Stage Iv ◽

Standard Of Care ◽

Phase Iii ◽

Primary Tumor Resection ◽

Primary Tumors ◽

Intention To Treat ◽

Unresectable Metastases

PURPOSE It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases. PATIENTS AND METHODS This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat. RESULTS Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm. CONCLUSION Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.

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Simultaneous laparoscopic liver resection: a single-center experience

Almanac of Clinical Medicine ◽

10.18786/20720505-2018-46-6-592-597 ◽

2018 ◽

Vol 46 (6) ◽

pp. 592-597

Author(s):

G. G. Akhaladze ◽

E. N. Grebenkin ◽

V. D. Chkhikvadze ◽

U. S. Stanojević ◽

S. V. Goncharov ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

Laparoscopic Liver Resection ◽

Tumor Resection ◽

Laparoscopic Approach ◽

Disease Group ◽

Primary Tumors ◽

Liver Resections ◽

Single Center Experience ◽

Metastatic Lesions

Background: About 15 to 25% of colorectal cancer patients have synchronous liver metastasis at diagnosis. In the recent years, the strategy of simultaneous removal of colorectal cancer and liver metastases has been preferred. Development of minimally invasive technologies in abdominal and hepatopancreatobiliary surgery allows for active advance to fully laparoscopic approach to these types of interventions.Aim: Comparative analysis of simultaneous and isolated laparoscopic liver resections performed in the Department of Surgery, Russian Research Center of Roentgenoradiology (Moscow).Materials and methods: We have analyzed intra- and postoperative results of 29 laparoscopic procedures for metastatic liver disease. Group 1 included 14 patients who had undergone simultaneous laparoscopic primary tumor resection and laparoscopic liver resection for metastatic disease. Group 2 included 15 patients who had undergone isolated laparoscopic liver resection for metastatic lesions.Results: Mean (± SD) blood loss in the simultaneous and isolated procedures groups was 469 ± 176 and 408 ± 124 mL, respectively (p = 0.2), whereas the duration of surgeries was 296 ± 107 and 204 ± 82 min, respectively (p = 0.01). Conversion rate in the isolated resection group was higher (26% vs. 14%). This difference is to be explained by the learning curve in laparoscopic liver surgery. All liver resections in both groups were carried out in R0 mode. No deaths and significant complications were seen in any of the groups.Conclusion: The study demonstrated feasibility and safety of simultaneous, fully laparoscopic liver resections, including those for difficult localization of primary tumors and metastatic lesions.

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Effect of primary tumor resection on survival in patients with metastatic colorectal cancer in the post-2000 era: A California Cancer Registry analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.504 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 504-504

Author(s):

Ana Milena Rodriguez Fahrni ◽

I-Yeh Gong ◽

Yingjia Chen ◽

Rosemary Cress ◽

Thomas John Semrad ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Metastatic Colorectal Cancer ◽

Cancer Registry ◽

Systemic Therapy ◽

Primary Tumor ◽

Tumor Resection ◽

Primary Tumor Resection ◽

Primary Tumors ◽

California Cancer Registry

504 Background: Resection of primary tumors in the setting of metastatic colorectal cancer (MCRC) is controversial. Fewer primary tumor resections are being performed due to the improved tumor response and disease control rates associated with modern systemic therapy. Recent studies suggest a survival benefit for patients with MCRC who had primary tumors resection prior to systemic therapy. This analysis evaluates the independent prognostic impact of primary tumor resection on overall survival (OS) for patients with MCRC using the California Cancer Registry (CCR). Methods: We queried the CCR for all patients with MCRC diagnosed between 2003 and 2010. Patients were categorized by whether or not they had primary tumor resection at time of diagnosis. Covariates included gender, age, race/ethnicity, socioeconomic status (SES), and rural-urban commuting area (RUCA) score of patients. Univariate comparisons were made using the Kaplan Meier method. Multivariate comparisons were performed using the Cox proportional hazards regression method. Results: 19,836 patients met the criteria for analysis of whom 11,566 (58%) had primary tumor resection. Primary tumor resection rates declined over this time period (63% in 2003 v. 52.8% in 2010, p<0.0001), varied by SES (55% v. 62%: lowest versus highest, p<0.001) and residence (63% in rural versus 58% for urban, P=0.0160). On multivariate analysis, overall survival was significantly better for patients that had primary tumor resection (HR: 0.467 [95% CI: 0.467-0.482]; p<0.0001). Survival was statistically longer in younger patients (HR: 1.385 for age 65-75, HR: 2.217 if greater than age 75), highest SES (HR: 0.869, p<0.0001), Hispanics (HR: 0.884, p<0001), and Asian/Pacific Islanders (HR:0.892, p<0.0001). Overall survival was worse for African Americans (HR:1.105, P=0.0001). Conclusions: Our study demonstrates the independent prognostic value on survival of primary tumor resection in patients with MCRC. There is significant variability of resection rates by SES and rural-urban residence. As analysis of CCR data cannot eliminate the influence of patient and provider biases, a prospective randomized trial is warranted.

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Relationship between the Expression of the Extracellular Matrix Genes SPARC, SPP1, FN1, ITGA5 and ITGAV and Clinicopathological Parameters of Tumor Progression and Colorectal Cancer Dissemination

Oncology ◽

10.1159/000343436 ◽

2013 ◽

Vol 84 (2) ◽

pp. 81-91 ◽

Cited By ~ 38

Author(s):

Luciano de Souza Viana ◽

Renato José Affonso ◽

Sandra Regina Morini Silva ◽

Marcos Vinicius Araujo Denadai ◽

Delcio Matos ◽

...

Keyword(s):

Colorectal Cancer ◽

Extracellular Matrix ◽

Tumor Progression ◽

Clinicopathological Parameters ◽

Cancer Dissemination

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SIRT1 promotes EMT, migration and invasion by regulating mTORC1/4E-BP1 in colorectal cancer

10.21203/rs.2.24358/v1 ◽

2020 ◽

Author(s):

Peifeng Liu ◽

Xiaojing Chen ◽

Shaolan Qin ◽

Yan Zhou ◽

Bo Yu ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Tumor Resection ◽

Underlying Mechanism ◽

Migration And Invasion ◽

Mtor Inhibition ◽

Primary Tumors ◽

Mesenchymal Transition

Abstract Background Metastasis, rather than primary tumors, was accounted for the most cases of cancer death in colorectal cancer(CRC). The understanding of the underlying mechanism associated with tumor metastasis would improve the patient’s miserable fate. SIRT1 has been identified to play a role in tumorigenesis and progression of malignant tumors, especially in keeping the characteristics of cancer stem cells(CSCs) in CRC. This study was conducted to investigate the role of SIRT1 in the regulation of metastasis and the underlying mechanism in colorectal cancer. Methods We detected the expression of SIRT1 in 42 metastatic CRC patients. The relationship between SIRT1 and time to metastasis was also analyzed. Then the SIRT1 activity was regulated to investigate the liver metastasis in BALB/c mice. SIRT1 was knocked down to evaluate the effect on migration and invasion. Besides, exogenetic SIRT1 to assess the motile ability by wound healing assay and transwell assay. We then further explored the underlying mechanism. Results SIRT1 was overexpressed in 67% CRC metastatic patients and associated with reduced time to metastasis. High SIRT1 activity by resveratrol was companied with more liver metastasis in vivo. SIRT1 deficiency increased E-cadherin, while reduced Vimentin and Snail, attenuated migration and invasion significantly in CT26 and SW620 cells. Meanwhile, the exogenetic SIRT1 induced epithelial–mesenchymal transition (EMT) and elevated the migratory ability in SW480 cells. Further studies demonstrated that mTORC1 related genes were elevated while 4E-BP1 decayed by SIRT1 overexpression. The promotion of metastasis induced by SIRT1 overexpression could be abolished by mTOR inhibition, while the stemness of cells was not changed. Conclusions Collectively, our findings illustrated that SIRT1 was a functional regulator in the promotion of metastasis in CRC via mTORC1-4E-BP1 axis. SIRT1 was a potential independent prognostic factor of CRC metastatic patients after tumor resection, which provided a promising treatment target in CRC.

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The Progression Potential of Peritoneal Dissemination Nodules From Gastrointestinal Tumors

International Surgery ◽

10.9738/cc21.1 ◽

2011 ◽

Vol 96 (4) ◽

pp. 352-357 ◽

Cited By ~ 3

Author(s):

Hayato Yamauchi ◽

Toshinaga Suto ◽

Wakako Kigure ◽

Hiroki Morita ◽

Toshihide Kato ◽

...

Keyword(s):

Primary Tumor ◽

Therapeutic Strategy ◽

Peritoneal Dissemination ◽

Mean Value ◽

Labeling Index ◽

Gastrointestinal Cancers ◽

Ki 67 ◽

Primary Tumors ◽

The Mean ◽

Cancer Dissemination

Abstract It is necessary to examine the characteristics of the dissemination nodules to establish a therapeutic strategy for peritoneal dissemination from digestive malignancy. Ki-67 expression as a proliferation marker in peritoneal dissemination nodules was investigated. The subjects were 15 patients with gastrointestinal cancers who underwent resection of the primary tumor and disseminated nodules. The expression of Ki-67 in both primary tumor and peritoneal dissemination nodule from each patient was evaluated by immunohistochemistry. Ki-67 labeling index in the original tumor was higher than that in the disseminated nodule in 13 of 15 patients (P < 0.0001). The mean value of Ki-67 labeling index was 42.2% in the 15 original tumors and 18.7% in the 15 disseminated nodules. Proliferative activity in the disseminated nodules was lower than that in the primary tumors. Further examination about characteristics of cancer dissemination is needed to treat patients with peritoneal metastasis.

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