Insight On Colorectal Carcinoma Infiltration by Studying Perilesional Extracellular Matrix

Abstract

The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential.

Linearized texture of three-dimensional extracellular matrix is mandatory for bladder cancer cell invasion

“…4l), with a fold of increase vs non-neoplastic ECM (Fig. 4m), similar to that previously reported in colorectal22 and ovarian cancers35.…”

“…Here we report novel evidence depicting differences and similarities in term of ECM ultrastructure between a non-tumoral and a MIBC human tissue, along with a number of detailed measurements of the geometry of the healthy lamina propria and muscularis propria. Second, the study showed that MIBC ECM is characterized by an increased degree of fibrils organization, in agreement with a recent report on colorectal carcinoma22. Third, using a synthetic scaffold this study showed that the linearized texture of fibrils is the main feature of the ECM associated with cell invasion.…”

“…Recent evidence has suggested that tumor-related extracellular environment may play a leading role, and it is not just a supporting actor over the initiation of the tumor; indeed, the dysregulation of the composition4 and stiffness21 of the ECM are associated with both the lack of asymmetric cellular division and of the differentiation of stem cells, and with the epithelial-mesenchymal transition of cancer stem cells as well, thus regulating tissue homeostasis and sustaining the onset and progression of cancer419. In agreement with these latter observations, we recently reported that an increased organization of ECM fibrils, but not biochemical composition, of the perilesional area of the colorectal carcinoma22 is associated with proliferation and infiltration of metastatic cancer cells23.…”

Towards integrating extracellular matrix and immunological pathways

“…Recently, proteomics approaches have also been used to analyze the ECM in tumor microenvironments, in particular for colorectal cancer. These studies have identified ECM signatures, including increased collagen deposition and cross-linking, in both humans (27) and mice (28), that promote tumor invasion and growth.…”

“…‘Omics’ approaches to survey gene transcription profiles or protein profiles of extracellular matrices from different pathological contexts will be useful is assessing changes in the abundance of ECM-related proteins. Several recent studies have begun to utilize mass spectrometry to generate protein profiles in the context of viral infection, lung fibrosis, and cancer revealing major differences in ECM composition compared to healthy controls (16,21–24,27,28). Particularly promising is the approach taken by Schiller et al in a recent study combining mass spectrometry and RNAseq to identify ECM and immunological pathways contributing to resolution of bleomycin-induced lung injury (24).…”