Correlation between biological and mechanical properties of extracellular matrix from colorectal peritoneal metastases in human tissues

Abstract

Peritoneal metastases (PM) are common routes of dissemination for colorectal cancer (CRC) and remain a lethal disease with a poor prognosis. The properties of the extracellular matrix (ECM) are important in cancer development; studying their changes is crucial to understand CRC-PM development. We studied the elastic properties of ECMs derived from human samples of normal and neoplastic PM by atomic force microscopy (AFM); results were correlated with patient clinical data and expression of ECM components related to metastatic spread. We show that PM progression is accompanied by stiffening of the ECM, increased cancer associated fibroblasts (CAF) activity and increased deposition and crosslinking in neoplastic matrices; on the other hand, softer regions are also found in neoplastic ECMs on the same scales. Our results support the hypothesis that local changes in the normal ECM can create the ground for growth and spread from the tumour of invading metastatic cells. We have found correlations between the mechanical properties (relative stiffening between normal and neoplastic ECM) of the ECM and patients’ clinical data, like age, sex, presence of protein activating mutations in BRAF and KRAS genes and tumour grade. Our findings suggest that the mechanical phenotyping of PM-ECM has the potential to predict tumour development.

Tissue Elasticity as a Diagnostic Marker of Molecular Mutations in Morphologically Heterogeneous Colorectal Cancer

“…In this study, increased breast cancer stiffness was correlated with the absence of estrogen, progesterone, and epidermal growth factor HER2 receptors on or within cells. The results of other studies [61][62][63] assessing the mechanical properties of cells with molecular mutations using atomic force microscopy showed consistency with our results. In particular, activation of KRAS expression in human breast epithelial MCF-10A cells resulted in increased cell stiffness [61].…”

“…A similar increase in cell and nuclear stiffness was observed in cardiomyocytes carrying the lamin A/C D192G gene mutation compared to control (wild-type lamin A/C cardiomyocytes) [62]. It is worth highlighting the research [63] in which an increase in stiffness of the extracellular matrix in human CRC cells was detected with the KRAS mutation, while with the BRAF mutation, the stiffness did not change, which is quite natural with our results. Despite the inability of C-OCE to measure the stiffness of individual cells and stromal fibers due to the maximum spatial resolution of 40-50 µm, previously, we established a correlation between the different structural arrangements of collagen bundles (by multiphoton second-harmonic generation microscopy) and breast cancer tissue stiffness (by C-OCE) before and after chemotherapy [64].…”

“…Despite the inability of C-OCE to measure the stiffness of individual cells and stromal fibers due to the maximum spatial resolution of 40-50 µm, previously, we established a correlation between the different structural arrangements of collagen bundles (by multiphoton second-harmonic generation microscopy) and breast cancer tissue stiffness (by C-OCE) before and after chemotherapy [64]. Consequently, the results obtained in the current study and discussed above [61][62][63] confirm the existence of some relationship between changes in tissue stiffness and molecular mutations of CRC and encourage comprehensive research on this topic.…”