Abstract
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.
Highlights
The liver is a frequent site for metastases from colorectal cancer, and despite that survival from this disease has substantially improved in the last several decades, the management of hepatic metastases is still difficult [27, 33]
Generation of mouse MC38 liver metastasis followed by isolation and enrichment of its extracellular matrix (ECM)
We did not analyze uninvolved tissues adjacent to the metastasis site, because such specimens cannot be considered as adequate controls due to recognized reprogramming of these tissues by host cells, including ECM alterations caused by cancer-associated fibroblasts and other stromal cells affected by cancer cells [2, 13]
Summary
The liver is a frequent site for metastases from colorectal cancer, and despite that survival from this disease has substantially improved in the last several decades, the management of hepatic metastases is still difficult [27, 33]. The extracellular matrix (ECM), composing the bulk of tumor stroma, has a leading role in progression of many cancers, including colorectal adenocarcinoma (6, 60a), and has been suggested to facilitate metastasis formation [60]. Despite significant progress to unravel the significance of the ECM remodeling in tumor biology [29], its impact on the liver metastatic milieu remains undefined. Extracellular matrix structural constituent conferring tensile strength. Extracellular matrix structural constituent Structural molecule activity Integrin binding Cell adhesion molecule binding. 9.96 8.19 Ͼ100 Ͼ100 Ͼ100 Ͼ100 7.24 7.23 Ͼ100 98.16 Ͼ100 Ͼ100 Ͼ100 Ͼ100 Ͼ100 Ͼ100 32.45 9.97
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