Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions

•Innate mesenchymal-stroma maintains a tumor-suppressive homeostatic equilibrium.•Fibroblastic-ECM interplay is referred to as stromal dynamic reciprocity.•Desmoplastic stromal dynamic reciprocity: a chronically upheld microenvironment.•Desmoplastic stromal dynamic reciprocity can be tumor restrictive and permissive.•Restoring innate stromal homeostatic signals is a potential cancer-impeding therapy.

Stromal dynamic reciprocity (SDR) consists of the biophysical and biochemical interplay between connective tissue elements that regulate and maintain organ homeostasis. In epithelial cancers, chronic alterations of SDR result in the once tumor-restrictive stroma evolving into a ‘new’ tumor-permissive environment. This altered stroma, known as desmoplasia, is initiated and maintained by cancer associated fibroblasts (CAFs) that remodel the extracellular matrix (ECM). Desmoplasia fuels a vicious cycle of stromal dissemination enriching both CAFs and desmoplastic ECM. Targeting specific drivers of desmoplasia, such as CAFs, either enhances or halts tumor growth and progression. These conflicting effects suggest that stromal interactions are not fully understood. This review highlights known fibroblastic-ECM interactions in an effort to encourage therapies that will restore cancer-restrictive stromal cues.

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