Hi,

Cancer associated fibroblasts (CAFs) are a subpopulation of cells that reside within the tumor microenvironment and promotes the transformation process by encouraging tumor growth, angiogenesis, inflammation, and metastasis. CAF-specific proteins serve as both prognostic markers and targets for anticancer drugs.

Other than he well known substances/factors you cited, proteins secreted by the tumor-associated CAF modify the microenvironment by contributing growth factors and proteases that degrade the extracellular matrix, and affect cell motility and adhesion. For example, CAF are able to secrete proteases (eg, MMP), protease inhibitors (eg. TIMP), and endoglycosidases (eg, heparanase). These proteins modify the ECM in what is thought to be a systematic manner. Osteopontin, galectin-3, transforming growth factor-β and matrix metalloproteinases (MMP) are important secreted proteins closely associated with cancer development.

In particular, MMP are expressed at higher levels by tumor-associated epithelial cells than by normal epithelial cells. These MMP revise the composition of the EMC by degrading the basement membrane and other ECM proteins. This increase in proteolytic activity may also act to support tumor malignancy. Extreme shifts in the inhibition of protease activity by plasminogen activation inhibitor-1 (PAI-1), either by its absence or by excessive levels, demonstrate an anti-angiogenic effect in mouse cells, while physiological levels of PAI-1 support angiogenesis. Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of MMP and may function to balance the protease activity of MMP to shift the balance from a pro-angiogenic to an inhibitory environment.

Obviously, there is a complex protease network in cancer and CAF are significantly involved in these pathways.

For more details in breast cancer: https://www.researchgate.net/publication/24001276_Protein_profile_analysis_of_the_breast_microenvironment_to_differentiate_healthy_women_from_breast_cancer_patients?ev=prf_pub

Article Protein profile analysis of the breast microenvironment to d...

Hello Dr. Mannello;

Thank you very much for remaining me the importance of various proteases. My main concern is the receptor for modified ECM, particularly integrin receptors. Tumor and CAF express various integrins. Both cells secrete proteases and matrix proteins. So complicated . Much work draw the clear network map---. But, your suggestions help me a lot to re-organize my thought.