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

Abstract

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.

Figure 1. Example of an epithelial cancer presenting high levels of desmoplastic stroma

Formalin-fixed and paraffin-embedded surgical normal (non-pathological) and lung cancer (neoplastic) samples were subjected to indirect immunofluorescence. Cellular vimentin is shown in red and is intended to denote both normal and desmoplastic stromal cells. Pan-cytokeratin is in green highlighting epithelial as well as neoplastic cells. DNA intercalating agent, Hoechst, was used to stain nuclei of all cell types and is shown in blue. Note that the neoplastic tissue is enriched with (red) dense stromal cells in comparison to its non-pathological counterpart.

Figure 2. Stromal Dynamic Reciprocity amid fibroblastic cell-ECM interactions in innate vs. desmoplastic homeostatic states

This model highlights the relationship between the cellular and ECM components of the mesenchymal-stroma demonstrating a dependence on this interplay to drive and maintain homeostatic states. The maintenance of the two homeostatic states is portrayed by the orbit-like arrows. The model depicts the phenotypical co-evolution of fibroblastic cells and their self-derived ECMs under the influences of a chronic assault (i.e. inflammation, cancer, etc.) suggesting possible restorative instances (i.e., therapies) of the innate, tumor-restrictive, stroma. Note that the cartoon includes a graphic representation of the cellular cytoskeleton which links, conveys and is modified in response to changes in both ECM and cellular states.

Figure 3. Stromal Dynamic Reciprocity model illustrating the likely peril of desmoplastic ablation

Innate SDR is the natural homeostatic stromal state in which tumor onset is repressed. When this environment is provisionally threatened (e.g., during infection or wounding), the innate homeostatic equilibrium transitions to a new, albeit short lived, homeostatic state: the acute SDR. In this homeostatic state, tissue repair is maintained until restoration is achieved. Following successful repair, and often after an acellular scar is formed, the system shifts or “tilts” back to the innate (tumor suppressive) homeostatic equilibrium. However, in the absence of wound resolution such as in the case of chronic inflammation and/or cancer, the acute SDR system is further sustained thus shifting the balance towards a third (chronic SDR) homeostatic equilibrium. During each of these transitions, extracellular and intracellular interactions are biophysically conveyed via the actomyosin cytoskeleton, which serves as a “conduit” transferring these mechanical cues amid cells and ECM. Note that this model suggests that a threat to the environment weakens the tumor restrictive (innate) capabilities in which, if not repaired (tilted back) in a timely fashion, cancer will be allowed to ensue (i.e., accompanied by a chronic/desmoplastic state). Additionally, this model proposes that ablation of chronic/desmoplastic SDR eliminates the possibility of shifting the system back to the innate tumor restrictive state.