The double edge sword of fibrosis in cancer

Abstract

Cancer-associated fibrosis is a critical component of the tumor microenvironment (TME) which significantly impacts cancer behavior. However, there is significant controversy regarding fibrosis as a predominantly tumor promoting or tumor suppressing factor. Cells essential to the generation of tissue fibrosis such as fibroblasts and mesenchymal stem cells (MSCs) have dual phenotypes dependent upon their independence or association with cancer cells. Cancer-associated fibroblasts and cancer-associated MSCs have unique molecular profiles which facilitate cancer cell cross talk, influence extracellular matrix deposition, and direct the immune system to generate a protumorigenic environment. In contrast, normal tissue fibroblasts and MSCs are important in restraining cancer initiation, influencing epithelial cell differentiation, and limiting cancer cell invasion. We propose this apparent dichotomy of function is due to (1) cancer mediated stromal reprogramming; (2) tissue stromal source; (3) unique subtypes of fibrosis; and (4) the impact of fibrosis on other TME elements. First, as cancer progresses, tumor cells influence their surrounding stroma to move from a cancer restraining phenotype into a cancer supportive role. Second, cancer has specific organ tropism, thus stroma derived from preferred metastatic organs support growth while less preferred metastatic tissues do not. Third, there are subtypes of fibrosis which have unique function to support or inhibit cancer growth. Fourth, depleting fibrosis influences other TME components which drive the cancer response. Collectively, this review highlights the complexity of cancer-associated fibrosis and supports a dual function of fibrosis which evolves during the continuum of cancer growth. (Translational Research 2019; 209:55À67) Cancer develops within a complex microenvironment critical to supporting tumor survival, growth, and metastasis. This tumor microenvironment (TME) is composed of a web of vasculature, extracellular matrix (ECM), stromal cells, immune cells, and soluble

Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

“…Single cell resolution also uniquely enables identification of rare cell types and analysis of combinatorial patterns of gene expression, both of which are necessary to reconstruct differentiation trajectories and to accurately define cellular heterogeneity between populations such as normal and malignant tissues, as well as to identify the mediators of interactions between different cell types. For example, pathological fibrosis underlies many prevalent diseases including cancer, where fibrosis is well recognised to be important for disease progression and metastasis (Chandler et al, 2019;Cox and Erler, 2014). It is broadly proposed that pro-fibrotic mediators secreted by cancer cells and infiltrating immune cells activate non-malignant stromal cells such as myofibroblasts to deposit collagen fibrosis (Cox and Erler, 2014).…”

Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer

“…Based on paracrine and juxtracrine signals, these stromal cells modulate cancer progression both directly and indirectly [17,19]. Furthermore, the production and deposition of excessive ECM, commonly known as brosis, can also foster tumor progression, even though the underlying mechanisms remain to be fully elucidated [20]. In non-small-cell lung carcinoma cells, pirfenidone, a pyridine compound with therapeutic potential for idiopathic pulmonary brosis, signi cantly inhibits brosis and decreases tumor growth when used in combination with carboplatin [21].…”

Cellular and Extracellular Components in Tumor Microenvironment and Their Application in Early Diagnosis of Cancers

“…However, cancerassociated fibrosis promotes cancer cell crosstalk and progression and is differently regulated in terms of four reasons: stromal source, stromal reprogramming under cancer mediation, fibrosis subtype, and the impact of other TME components [93]. In in vivo and vitro studies, chemotherapy and radiation therapy are also drivers of fibrosis via generating the hypoxia microenvironment and activating the immune system [93]. The impact of cancer fibrosis on cancer behavior is controversial.…”