Carcinoma-Associated Fibroblasts Are a Promising Therapeutic Target

Abstract

Human carcinomas frequently exhibit significant stromal reactions such as the so-called “desmoplastic stroma” or “reactive stroma”, which is characterised by the existence of large numbers of stromal cells and extracellular matrix proteins. Carcinoma-associated fibroblasts (CAFs), which are rich in activated fibroblast populations exemplified by myofibroblasts, are among the predominant cell types present within the tumour-associated stroma. Increased numbers of stromal myofibroblasts are often associated with high-grade malignancies with poor prognoses in humans. CAF myofibroblasts possess abilities to promote primary tumour development, growth and progression by stimulating the processes of neoangiogenesis as well as tumour cell proliferation, survival, migration and invasion. Moreover, it has been demonstrated that CAFs serve as a niche supporting the metastatic colonisation of disseminated carcinoma cells in distant organs. Their contribution to primary and secondary malignancies makes these fibroblasts a potential therapeutic target and they also appear to be relevant to the development of drug resistance and tumour recurrence. This review summarises our current knowledge of tumour-promoting CAFs and discusses the therapeutic feasibility of targeting these cells as well as disrupting heterotypic interactions with other cell types in tumours that may improve the efficacy of current anti-tumour therapies.

Fibroblast-derived Neuregulin 1 Promotes Compensatory ErbB3 Receptor Signaling in Mutant BRAF Melanoma

“…These data are consistent with the ability of ErbB3-targeting agents to increase the efficacy and duration of response of RAF inhibitors in vivo (15) and underscore the use of ErbB3-targeting agents to reduce the protective effects of fibroblast-derived NRG1 on RAF-inhibited melanoma cells. Although pertuzumab and seribantumab target ErbB3/ErbB2 signaling by preventing ErbB3/ErbB2 dimerization or the binding of NRG1 to ErbB3, respectively, other agents may be developed to directly sequester NRG1 (45) or to directly target CAFs (46). Our findings also have relevance to other tumor types in which ErbB3 has been implicated in driving resistance to targeted inhibitors (19,20).…”

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…The realization of these biological links justifies the design of clinical studies based on the targeting of CAF (and, more generally, reversal of the attributes of a protumorigenic microenvironment) in addition to targeting cancer cells in order to create a tumor-resistant environment that inhibits malignant phenotypes in diseased epithelial cells (Takebe et al 2013;Togo et al 2013;Zhou et al 2015). Such clinical studies can now be envisioned based on the findings from experimental studies with agents directed against fibroblast-specific proteins (FAP, COL11A1, and MFAP5) or signaling pathways exemplified in CAFs (TGF-β, hedgehog, Notch, FGF, PDGF, or C-X-C motif ligand 2 [CXCL2]/CXCR4 signaling).…”

Tumor Cell–Targeted Delivery of Nanoconjugated Oligonucleotides in Composite Spheroids

“…***p < 0.001 compared with all other groups. therapeutic target [28,29]. However, it has also been recently suggested that not all of the fibroblasts within a tumor are harmful to the patient; carcinoma associated fibroblasts are able to express both tumor promoting and tumor suppressing molecules simultaneously [4,5].…”