Table 3.

CAFs regulate cancer cell behavior.

Effects	Mechanisms	References
Tumor enhancing
Generate desmoplastic stroma	High fibrotic stroma-tumor ratio	[372,460,461,462,463,464,489]
	Immunosuppressive cytokines	[413]
	TGFβ singling activation by paladin-mediated F-actin organization	[413]
	Tumor invasion toward vasculature	[412]
	application of traction force and stroma remodeling supporting invasion	[414]
	Increasing stroma stiffness-initiating cancer cell protumorigenic signals, mechanical stress on nuclei, DNA damage, genomic instability	[83,415,418,429]
	Upregulation of transcription factors, EMT and cancer cell stemness	[424]
	Collapse of blood vessels accessing tumors decreases oxygen tension, pH, immune cells, therapy access and angiogenesis	[39,230,411,419]
	Secreting cytokines	[420]
	Initiating anti-apoptotic and treatment resistance signaling through binding of upregulated integrins	[134,137,139,425,426,427,428]
	Aging-induced collagen stiffening, reduced ROS DNA damage response and targeted therapy resistance	[29,416,417]
Secrete growth factors cytokines and chemokines
	TGFβ and Wnt/β-catenin signaling	[445]
	Podoplanin and surface membrane protein signaling	[446]
	Metabolism	[447]
	Proliferation	[215]
	Angiogenesis	[447,457]
	Induce EMT	[80,287,448]
	Proliferation, migration, invasion, and metastasis	[442,449,451,452,457,474,475,482,489]
	Immune system modulation	[181,447,450,457,459,474,484,485,486,489,490,491,492]
	Loss of CAF androgen receptor expression in prostate cancer	[454,455]
SHH signaling	angiogenesis, fibrosis, immune evasion, and neuropathic pain	[470,471]
Notch1 signaling	Increased cancer cell stemness, microvessel density, neoangiogenesis	[497]
Wnt, Hippo, TGFβ, MAPK signaling	Proliferation, invasion, metastasis	[473]
Epigenetic reprogramming	Migration, inhibited apoptosis, treatment resistance	[477,478,479,480,481]
Slowing of cancer cell circadian cycling periods	Slowing of cancer metabolic parameters of glycolytic capacity, reserve, respiration, ATP production, mitochondrial coupling efficiency, decreased apoptosis, increased viability and chemoresistance	[333]
Prime neutrophils	Activate MSCs to CAFs	[493]
Tumor suppressive	High stroma–tumor ratio	[465,466,467,468]
	Active extratumoral fibroblasts with high expression of fibrosis and cellular movement genes	[130,469]
Notch1 signaling	Inhibiting stemness	[494]
SHH signaling	Tumor differentiation, immune surveillance, T cell immunity, decreased angiogenesis and αSMA-expression	[467,498,499,500,501]
Increased CAF stem cell characteristics	Inhibiting proliferation and angiogenesis	[75,124,125,495,496]
IL-8	Inhibiting proliferation of some cancer types, not others	[439]
Rho signaling	Inhibiting tumor proliferation	[110]
CAF-expressed collagen I	Suppressing tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals	[503]
Meflin-expressing αSMA-depleted CAFs	Inhibiting TGFβ-induced fibrosis through inhibition of collagen crosslinking	[496,504]
IKKβ/NFκB	Negatively regulates HGF and TGFβ expression, inhibits tumor growth, promotes tumor cell death and suppresses regulatory T cells	[502]
miR-10-5p, miR-206	Suppressing proliferation, migration, cytokine levels	[272,505]