Table 2.

Reciprocal effects of cancer cells and stromal fibroblasts.

Actions by Cancer Cells	Effects on Fibroblasts	Refs.	Actions by Fibroblasts	Effects on Cancer Cells	Refs.
TME has low pH, hypoxia, glycolytic oxidation, stiffness, inflammation, ionic gradients and high concentrations of chemokines and cytokines	- Environment fosters NF and other local or recruited cell conversions to CAFs - Cancer cells act through soluble factors, direct contact, export of exosomes, direct fusion with MSCs and fibroblasts	[205,206]	Converted CAFs	- Favor tumor growth and progression - Preparation of the pre-metastatic niche	[205,206]
Tumor hypoxia from low vessel count	Stimulate stellate cell periostin, collagen I, fibronectin, VEGF secretion	[179]	- Pancreatic stellate cells induce fibrinogenesis, deposit periostin-rich matrix around capillaries, secrete VEGF - Tumor residing stellate cells circulate to distant sites	- Stimulate angiogenesis in the primary tumor. Induce endostin production by cancer cells - Facilitate tumor seeding, survival and proliferation in metastatic sites	- [178,179] - [180]
Release pro-inflammatory cytokines	Attract BM MSCs to the tumor	[20,175,176,177]	Newly arrived MSCs release cytokines	Released cytokines promote malignant behavior in the tumor	[175,176,177]
Cancer cells release FGF-2, VEGF, PDGF, EGF, TGFβ, CCL2, CCL5, IL-6, IL-8,	- Activate fibroblasts - Modulate CAF gene expression - Modulate CAF metabolism	- [182,183,184] - [185,186] - [187,188]	Activated fibroblasts secrete cytokines	Promote proliferation, motility, and survival of epithelial cancer cells but not dormant tumor initiating cells	[189,190]
Cancer cell co-cultivation or conditioned medium “educate” BM MSCs that home to tumors	BM MSCs increase OPN, IL-8, FGF-2 secretion, decrease vimentin, αSMA expression	[175]	OPN, IL-8, FGF-2 attract cancer cells; vimentin, αSMA decrease MSC migration, keep them in the TME	Promote cancer progression	[175]
BC cells overexpress CD147 transmembrane glycoprotein.	CD147 promotes transformation of fibroblasts to CAFs	[191]	CD147-transformed fibroblasts express αSMA	Induce EMT in co-cultured BC cells	[191]
Cancer cells induce ratio-dependent secretory senescence in co-cultivated BM stroma	BC cells ratio-dependent stromal secretion of IL-6 and IL-8	[138]	Stroma incubated with cancer cells secrete cytokines	Cytokines induce positive feedback loop for cancer cells growth stimulation	[138]
Breast cancer cells transform nearby adipocytes into adipocyte-derived fibroblasts (ADFs) through secretion of Wnt3a	ADFs reactivate Wnt/β-catenin, express FSP-1, are more migratory/invasive	[192]	ADFs secrete fibronectin and collagen I	Increase invasion in co-cultivated tumor cells	[192]
Tumor cells co-cultured with obese animal and visceral ADFs induce inflammation	Increase IL-6, MIP-2 and MCP-1 expression in obese and visceral ADFs	[196]	Tumor-stimulated ADFs attract CD3+ T-lymphocytes and F4/80+ macrophages	Promote growth and dissemination of ovarian epithelial cells in vivo	[196]
Breast cancer cells modify adjacent adipose tissue MSCs	Cancer-adjacent MSCs upregulate BDNF, NOTCH1, SOX9, vimentin, VCAM1, downregulate growth differentiation factor 15 (GDF15), IGF1, MMP2, PDGFRβ, TGFβ3, BMP4 and have increased proliferative potential	[203]	- Cancer associated adipose MSCs enhance BC cell aggressiveness - Contribute to pericytes and adipocytes populating the TME	Enhanced tumorigenicity, collective cell invasion, EMT+ invasive front tumor cells, adjacent nerve invasion in xenografts	[203,204]
Genetic changes in primary tumor cells induce genetic and gene expression changes in stromal fibroblasts through ROS.	- Fibroblasts increase ECM proteins and chemokines	- [198,199,200]	- Tumor-induced genetically modified stromal and BM fibroblasts increase versican, tenascin, BDFN, CCL5, CXCL5, and CXCL16 - Frequency of normal breast CD34+ fibroblasts, markedly decreases, and that of αSMA+ fibroblasts increases - CAFs have higher levels of RhoA and Rac1 than NFs	- Promote tumor progression - Associated with higher stage and lower overall and disease-free survival - Active in invasion of cancer cells	[198,199,200] - [201] - [202]