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Abstract
The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expression. EMT was confirmed by gene expression profiling, with the most represented biological processes in CRLM-seeded scaffolds involving demethylation, deacetylation, a cellular response to stress metabolic processes, and a response to the oxygen level and starvation. HT-29 cells cultured in cancer-specific 3D microenvironments showed a reduced response to treatment with 5-fluorouracil and 5-fluorouracil combined with Irinotecan when used at a standard IC50 (as determined in the 2D culture). Our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the metastatic microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of CRLM progression and assessing the response to chemotherapy agents.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide and is ranked as the second leading cause of cancer-related deaths [1]
Cell behavior in liver metastasis in vitro, we demonstrated that tumor-derived scaffolds (CRC and cancer liver metastasis (CRLM)) supported a more proliferative phenotype compared to the respective normal counterpart, with seeded colorectal cancer (CRC) scaffolds showing an even higher proliferation rate compared to CRLM scaffolds
Our results demonstrate that the response of 3D-cultured CRC cells to 5-FU and FOLFIRI administration was affected by the complex microenvironment provided by the tissue-specific decellularized scaffolds
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide and is ranked as the second leading cause of cancer-related deaths [1]. The liver is the most common site of CRC metastasis as the majority of intestinal mesenteric drainage enters the hepatic portal venous system [2] and, at the time of diagnosis, up to 25% of patients have a synchronous liver metastasis. Any hypothesis to explain why the liver is a main target of CRC metastasis cannot be restricted to the fact that the liver represents the first capillary bed to which disseminated. According to the ‘seed and soil’ hypothesis, some distant organs provide a more favorable micro-environment for the colonization of cancer cells than others [4]. The genetic characteristics of tumor cells are essential for conferring a metastatic-prone phenotype, crucial micro-environmental cues cannot be disregarded in cancer cell colonization and metastasis
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