Abstract
Collagen, the main non-cellular component of the extracellular matrix (ECM), is profoundly reorganized during tumorigenesis and has a strong impact on tumor behavior. The main source of collagen in tumors is cancer-associated fibroblasts. Cancer cells can also participate in the synthesis of ECM; however, the contribution of both types of cells to collagen rearrangements during the tumor progression is far from being clear. Here, we investigated the processes of collagen biosynthesis and remodeling in parallel with the transcriptome changes during cancer cells and fibroblasts interactions. Combining immunofluorescence, RNA sequencing, and second harmonic generation microscopy, we have explored the relationships between the ratio of epithelial (E) and mesenchymal (M) components of hybrid E/M cancer cells, their ability to activate fibroblasts, and the contributions of both cell types to collagen remodeling. To this end, we studied (i) co-cultures of colorectal cancer cells and normal fibroblasts in a collagen matrix, (ii) patient-derived cancer-associated fibroblasts, and (iii) mouse xenograft models. We found that the activation of normal fibroblasts that form dense collagen networks consisting of large, highly oriented fibers depends on the difference in E/M ratio in the cancer cells. The more-epithelial cells activate the fibroblasts more strongly, which correlates with a dense and highly ordered collagen structure in tumors in vivo. The more-mesenchymal cells activate the fibroblasts to a lesser degree; on the other hand, this cell line has a higher innate collagen remodeling capacity. Normal fibroblasts activated by cancer cells contribute to the organization of the extracellular matrix in a way that is favorable for migratory potency. At the same time, in co-culture with epithelial cancer cells, the contribution of fibroblasts to the reorganization of ECM is more pronounced. Therefore, one can expect that targeting the ability of epithelial cancer cells to activate normal fibroblasts may provide a new anticancer therapeutic strategy.
Highlights
It is known that the development and progression of malignant tumors, as well as their therapeutic resistance, depends on the intrinsic characteristics of the cancer cells and to a significant degree on the tumor stroma [1,2]
RNA-sequencing, and second harmonic generation (SHG) microscopy, we demonstrated phenotypic, transcriptomic, and functional changes in the fibroblasts upon their activation by cancer cells, and this correlated with the intrinsic migratory capacity of the cancer cells
In a search for the cellular mechanisms underlying the interaction of cancer cells and normal fibroblasts, we examined various colorectal cancer cell lines for their epithelial/mesenchymal states
Summary
It is known that the development and progression of malignant tumors, as well as their therapeutic resistance, depends on the intrinsic characteristics of the cancer cells and to a significant degree on the tumor stroma [1,2]. There are no completely curative strategies and some of them, in case of lysyl oxidase homolog 2 LOXL2 inhibitors, have failed clinical trials [3,4]. Taken together, it says that our knowledge in this field is insufficient, and the search for novel stromal targets should be carried out. Cancer-associated fibroblasts (CAFs) supposedly play an important role in the formation of the specific tumor microenvironment. The expression of the most commonly used markers—α-smooth muscle actin (aSMA), fibroblast-activating protein (FAP), and platelet-derived growth factor receptors A/B (PDGFRa/b)—varies strongly among CAF subpopulations, reflecting the highly heterogeneous nature and plasticity of CAFs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
