Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern

AbstractClaudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.

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Histologically Verified Biliary Invasion was Associated with Impaired Liver Recurrence-Free Survival in Resected Colorectal Cancer Liver Metastases

Scandinavian Journal of Surgery ◽

10.1177/1457496918812237 ◽

2018 ◽

Vol 108 (3) ◽

pp. 201-209 ◽

Cited By ~ 2

Author(s):

P. Reijonen ◽

P. Österlund ◽

H. Isoniemi ◽

J. Arola ◽

A. Nordin

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Liver Metastasis ◽

Liver Metastases ◽

Recurrence Free Survival ◽

Colorectal Cancer Liver Metastases ◽

Free Survival ◽

Colorectal Cancer Liver Metastasis ◽

Liver Recurrence ◽

Disease Free

Background and Aims: The impact of biliary invasion on recurrence and survival, after resection of colorectal cancer liver metastases, is not well known as publications are limited to small patient series. The aim was to investigate if biliary invasion in liver resected patients associated with liver relapses and recurrence-free survival. Secondary endpoints included association with other prognostic factors, disease-free survival and overall survival. Materials and Methods: All patients with histologically verified biliary invasion (n = 31, 9%) were identified among 344 patients with liver resection between January 2009 and March 2015. Controls (n = 78) were selected from the same time period and matched for, among others, size and number of colorectal cancer liver metastasis. Results: Median liver recurrence-free survival was significantly shorter in patients with biliary invasion than in controls (15.3 months versus not reached; p = 0.031) and more relapses were noted in the liver (61.3% versus 33.3%; p = 0.010), respectively. In univariate analyses for liver recurrence-free survival, biliary invasion was the only significant prognostic factor; p = 0.034. There were no statistical differences in disease-free and overall survival between the groups. Conclusion: Biliary invasion was associated with higher liver recurrence rates and shorter liver recurrence-free survival in patients with resected colorectal cancer liver metastasis.

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Radiomics and Radiogenomics in Evaluation of Colorectal Cancer Liver Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2021.689509 ◽

2022 ◽

Vol 11 ◽

Author(s):

Yun Wang ◽

Lu-Yao Ma ◽

Xiao-Ping Yin ◽

Bu-Lang Gao

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Liver Metastases ◽

Texture Features ◽

Biological Properties ◽

Imaging Features ◽

Current Application ◽

Colorectal Cancer Liver Metastases ◽

Colorectal Cancer Liver Metastasis ◽

Non Invasive

Colorectal cancer is one common digestive malignancy, and the most common approach of blood metastasis of colorectal cancer is through the portal vein system to the liver. Early detection and treatment of liver metastasis is the key to improving the prognosis of the patients. Radiomics and radiogenomics use non-invasive methods to evaluate the biological properties of tumors by deeply mining the texture features of images and quantifying the heterogeneity of metastatic tumors. Radiomics and radiogenomics have been applied widely in the detection, treatment, and prognostic evaluation of colorectal cancer liver metastases. Based on the imaging features of the liver, this paper reviews the current application of radiomics and radiogenomics in the diagnosis, treatment, monitor of disease progression, and prognosis of patients with colorectal cancer liver metastases.

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Surgical Treatment of Colorectal Cancer Liver Metastases

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.52 ◽

2012 ◽

pp. 209-212

Author(s):

Steven A. Curley

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Treatment Strategies ◽

Stage Iv ◽

Hepatic Arterial Infusion ◽

Arterial Infusion ◽

Colorectal Cancer Liver Metastases ◽

Stage Iv Colorectal Cancer ◽

Cancer Metastases ◽

Colorectal Cancer Metastases

Overview: Treatment strategies for patients with stage IV colorectal cancer have changed markedly in the last decade. Patients with colorectal cancer metastases to the liver have always been a fascinating group to consider biologically and for local-regional treatment strategies. In the late 1980s through the 1990s, resection was performed for a select subset of patients who had resectable disease. However, a high proportion of patients had bilobar unresectable disease and were treated with either 5-fluorouracil–based systemic chemotherapy or implanted hepatic arterial infusion pumps. The advent of the new millennium was associated with the availability of several new cytotoxic and biologic agents active in colorectal cancer. These agents have completely changed the approach to the treatment of patients with colorectal cancer liver metastases and thus have increased the complexity of the decision-making process for treatment of these patients.

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Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia

British Journal of Cancer ◽

10.1038/sj.bjc.6601727 ◽

2004 ◽

Vol 90 (7) ◽

pp. 1429-1436 ◽

Cited By ~ 118

Author(s):

F Stessels ◽

G Van den Eynden ◽

I Van der Auwera ◽

R Salgado ◽

E Van den Heuvel ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Growth Pattern ◽

Breast Adenocarcinoma ◽

Colorectal Cancer Liver Metastases

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Hepatectomy followed by adjuvant chemotherapy with capecitabine plus oxaliplatin for three months for colorectal cancer liver metastases: A multicenter phase 2 study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15015 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15015-e15015

Author(s):

Hiroki Hashida ◽

Hironaga Satake ◽

Hiroaki Tanioka ◽

Yasuhiro Miyake ◽

Shinichi Yoshioka ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Liver Metastases ◽

Statistical Power ◽

Curative Resection ◽

Treatment Strategies ◽

Completion Rate ◽

Open Label ◽

Colorectal Cancer Liver Metastases ◽

The Mean

e15015 Background: Hepatic resection is one of the treatment strategies for resectable colorectal cancer liver metastases (CLM). The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable CLM is still unclear. Adjuvant chemotherapy consisting of capecitabine plus oxaliplatin (CapeOx) appears to be equivalent to FOLFOX in patients with stage III colon cancer. Furthermore, some studies suggest that adjuvant chemotherapy for three months after curative resection for stage II/III colorectal cancer has equivalent efficacy to adjuvant chemotherapy for 6 months. We initiated a multi-institutional, single-arm, open label, phase II trial to confirm the feasibility of adjuvant CapeOx for three months for post curative resection of CLM. Methods: Patients received one course of capecitabine followed by four courses of CapeOx for a total five courses (15 weeks) as adjuvant chemotherapy after curative resection of CLM. CapeOx consisted of a 2-hour intravenous infusion of oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle. The primary endpoint was completion rate of adjuvant chemotherapy. We set a threshold completion rate of protocol treatment of 45% and an expected completion rate of 70%. Given a one-sided α of 0.1 and statistical power of 80%, a minimum of 25 patients was required. Results: From May 2013 to November 2015, Twenty-eight patients were enrolled from six institutions: median age 69.5y, 54% male, 78.5% left-sided primary. Of the patients, 15 were synchronous metastases and 13 were metachronous. The locations of the metastases were unilobar in 20 patients and bilobar in 8. The mean number of lesions resected was two (range, 1 to 4). The mean size of largest tumor was 31 mm (range, 2 to 112 mm). Among the 28 patients, 20 (71.4 %: 95% CI, 53.6 to 89.3%) completed the protocol treatment. The most common grade 3 or 4 toxicities were neutropenia (29%). No treatment related death was observed. Conclusions: Adjuvant CapeOx for three months for post curative resection of CLM was feasible. Clinical trial information: UMIN000011164.

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Changes in liver surgery for colorectal cancer liver metastases under neoadjuvant treatment strategies

European Surgery ◽

10.1007/s10353-004-0095-2 ◽

2004 ◽

Vol 36 (5) ◽

pp. 317-321 ◽

Cited By ~ 9

Author(s):

T. Gruenberger ◽

B. Schuell ◽

H. Puhalla ◽

E. Schwanzer ◽

M. Bodingbauer ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Liver Surgery ◽

Neoadjuvant Treatment ◽

Treatment Strategies ◽

Colorectal Cancer Liver Metastases

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Predictive Efficacy of MiR-125b-5p, MiR-17-5p, and MiR-185-5p in Liver Metastasis and Chemotherapy Response Among Advanced Stage Colorectal Cancer Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.651380 ◽

2021 ◽

Vol 11 ◽

Author(s):

Daniel Sur ◽

Loredana Balacescu ◽

Simona S. Cainap ◽

Simona Visan ◽

Laura Pop ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Liver Metastases ◽

Treatment Response ◽

Metastatic Potential ◽

Chemotherapy Response ◽

Tumor Tissues ◽

Non Coding Rnas ◽

Colorectal Cancer Patients ◽

Plasma Collection

MicroRNAs (miRNAs), a class of small non-coding RNAs represent potential biomarkers for colorectal cancer (CRC). The study hypothesized that miRNAs associated with liver metastases may also contribute to assessing treatment response when associated to plasma exosomes. In this study, we used two sets of biological samples, a collection of tumor tissues harvested from patients with CRC with and without liver metastases, and a collection of plasma from CRC patients with and without response to FOLFOX4/FOLFIRI regimens. We investigated 10 target miRNAs in the tissue of 28 CRC patients and identified miR-125b-5p, miR-17-5p, and miR-185-5p to be associated with liver metastasis. Further, we investigated the three miRNAs at the exosomal level in a plasma collection to test their association with chemotherapy response. Our data suggest that the elevated plasma levels of miR-17-5p and miR-185-5p could be predictive of treatment response. Overexpression of miR-17-5p and underexpression of miR-125b-5p and miR-185-5p in CRC tissue seem to be associated with metastatic potential. On the other hand, an increased expression of miR-125b-5p in plasma exosomes was potentially correlated with a more aggressive CRC phenotype.

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Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases

Cancers ◽

10.3390/cancers14010241 ◽

2022 ◽

Vol 14 (1) ◽

pp. 241

Author(s):

Valentina Giannini ◽

Laura Pusceddu ◽

Arianna Defeudis ◽

Giulia Nicoletti ◽

Giovanni Cappello ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

First Line ◽

Colorectal Cancer Liver Metastases ◽

Predictive Values ◽

Progression Of Disease ◽

Folfox Chemotherapy ◽

Colorectal Cancer Patients ◽

Sensitivity Specificity ◽

Radiomics Signature

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies.

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Establishment of an Antibody Specific for AMIGO2 Improves Immunohistochemical Evaluation of Liver Metastases and Clinical Outcomes in Patients with Colorectal Cancer

10.21203/rs.3.rs-934233/v1 ◽

2021 ◽

Author(s):

Keisuke Goto ◽

Mitsuhiko Osaki ◽

Runa Izutsu ◽

Hiroshi Tanaka ◽

Ryo Sasaki ◽

...

Keyword(s):

Colorectal Cancer ◽

Monoclonal Antibody ◽

Liver Metastasis ◽

Liver Metastases ◽

Clinical Outcomes ◽

Transmembrane Protein ◽

Amino Acid Level ◽

Immunohistochemical Analysis ◽

Type I ◽

Tissue Samples

Abstract Instruction: The human amphoterin-induced gene and open reading frame (AMIGO) was identified as a novel cell adhesion molecule of type I transmembrane protein. AMIGO2 is one of three members of the AMIGO family (AMIGO1, 2, and 3), and the similarity between them is approximately 40% at the amino acid level. We have previously shown that AMIGO2 functions as a driver of liver metastasis. Immunohistochemical analysis of AMIGO2 expression in colorectal cancer (CRC) using a commercially available anti-AMIGO2 mouse monoclonal antibody clone sc-373699 (sc mAb) correlated with liver metastasis and poor prognosis. However, the sc mAb was found to be cross-reactive with all three molecules in the AMIGO family. Methods: We generated a rat monoclonal antibody clone rTNK1A0012 (rTNK mAb) for human AMIGO2. The rTNK mAb was used to re-evaluate the association between AMIGO2 expression and liver metastases/clinical outcomes using the same CRC tissue samples previously reported with sc mAb. Results: Western blot analysis revealed that a rTNK mAb was identified as being specific for AMIGO2 protein and did not cross-react with AMIGO1 and AMIGO3. The rTNK mAb and sc mAb showed higher AMIGO2 expression, which correlates with a high frequency of liver metastases (65.3% and 47.5%, respectively), while multivariate analysis showed that AMIGO2 expression was an independent prognostic factor for liver metastases (p = 7.930E-10 and p = 1.707E-5). The Kaplan-Meier analyses showed that the rTNK mAb (p = 0.004), but not sc mAb (p = 0.107), predicted worse overall survival in patients with high AMIGO2 expression. The relationship between AMIGO2 expression and poor disease-specific survival showed a higher level of significance for rTNK mAb (p = 0.00004) compared to sc mAb (p = 0.001). Conclusion: These results indicate that the developed rTNK1A0012 mAb is an antibody that specifically recognizes AMIGO2 by immunohistochemistry and can be a more reliable and applicable method for the diagnostic detection of liver metastases and worse prognosis in patients with high AMIGO2-expressing CRC.

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