Collateral Damage Intended—Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy

Abstract

After oncogenic transformation, tumor cells rewire their metabolism to obtain sufficient energy and biochemical building blocks for cell proliferation, even under hypoxic conditions. Glucose and glutamine become their major limiting nutritional demands. Instead of being autonomous, tumor cells change their immediate environment not only by their metabolites but also by mediators, such as juxtacrine cell contacts, chemokines and other cytokines. Thus, the tumor cells shape their microenvironment as well as induce resident cells, such as fibroblasts and endothelial cells (ECs), to support them. Fibroblasts differentiate into cancer-associated fibroblasts (CAFs), which produce a qualitatively and quantitatively different extracellular matrix (ECM). By their contractile power, they exert tensile forces onto this ECM, leading to increased intratumoral pressure. Moreover, along with enhanced cross-linkage of the ECM components, CAFs thus stiffen the ECM. Attracted by tumor cell- and CAF-secreted vascular endothelial growth factor (VEGF), ECs sprout from pre-existing blood vessels during tumor-induced angiogenesis. Tumor vessels are distinct from EC-lined vessels, because tumor cells integrate into the endothelium or even mimic and replace it in vasculogenic mimicry (VM) vessels. Not only the VM vessels but also the characteristically malformed EC-lined tumor vessels are typical for tumor tissue and may represent promising targets in cancer therapy.

Vasculogenic mimicry in carcinogenesis and clinical applications

“…TAFs are important factors in tumor growth and VM formation [73][74][75]. Some studies have demonstrated that TAFs are required for tumor vascularization via various signaling pathways in malignant tumors [76][77][78]. In 2016, Yang et al showed that the conditioned medium of tumor-associated fibroblasts (CM-TAMs) could promote VM formation in vitro through secreting TGF-β and SDF1, and the expression of VE-cadherin, MMP-2, and laminin5γ2 was increased by TGF-β and SDF1 in hepatocellular carcinoma [73].…”

“…Furthermore, CSCs also play a significant role in the design of novel anti-tumor therapies [11][12][13]. The latest findings reveal that lncRNAs such as LINC00339, LINC00312, and MALAT1 could also be promising targets in anti-VM therapy [16,26,77]. Therefore, the clinical application of therapeutic strategies by targeting tumor VM needs further investigation in the future.…”

Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor

“…Previous studies has proved that angiogenesis can be weakened by inhibiting CAF-secreted cytokines and microvessels in the tumor can be normalized to increase micelles penetration. 69,70 On this basis, highly enhanced micelle retention was observed in TC therapy ( Figure 6), which was thought to correspond to IFP reduction and microvessels normalization. The control and tranilast groups also showed high radiant efficiency for remarkable EPR effect in breast cancer as a result of high vascular density.…”

Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts

“…Orchestrating TC survival and progression, the tumor microenvironment (TME) is characterized by the biochemical composition and biophysical properties of the extracellular matrix (ECM) by ECM-sequestered cytokines, as well as by the mutual interactions of the different cellular components, such as TCs, cancer-associated fibroblasts, immune cells, and ECs [ 20 , 21 ]. Within the TME, all these cells communicate through several juxtacrine and paracrine mechanisms.…”