Table I.
Factors that maintain tumor indolence and mechanisms mediating a switch into aggressive disease.
Indolence factor | First author, year | Escape mechanism/aggressiveness induction | (Refs.) |
---|---|---|---|
Low mutation rate | Taylor et al, 2010 | Additional genetic aberrations | (30) |
Bonollo et al, 2020 | CAF effects | (88) | |
Aggarwal et al, 2018 | Epigenetic modifications | (50) | |
Slow proliferation | Taylor et al, 2010 | Additional genetic aberrations | (30) |
Bonollo et al, 2020 | CAF effects | (88) | |
Sugiura et al, 2021 | Cell cycle gene hypermethylation | (43) | |
Sejda et al, 2020 | Neurotrophic signaling | (98) | |
Androgen dependence | Taylor et al, 2010; | Additional genetic aberrations | (30,37) |
Beltran et al, 2016 | |||
Blom et al, 2019 | TME factors | (89) | |
Ngollo et al, 2014; | Epigenetic adaptation | (40,59) | |
Fu et al, 2006 | |||
Nutrient scarcity/hypoxia | West et al, 2001 | VEGF upregulation | (129) |
Ngollo et al, 2014; | Epigenetic adaptation | (40,48) | |
Ge et al, 2020 | |||
Taylor et al, 2010; | Additional genetic aberrations | (30,37) | |
Beltran et al, 2016 | |||
Bonollo et al, 2020 | Crosstalk with CAFs | (88) | |
Immunosurveillance | Ness et al, 2014 | Dysfunctional TILs | (71) |
Nardone et al, 2016 | High regulatory Foxp3+ | (75) | |
Mariathasan et al, 2018 | High M2 macrophages | (77) | |
Heninger et al, 2016 | MHC Class 1 silencing | (78) | |
Fibroblast/stromal-induced inhibition of tumor growth | Blom et al, 2019 | CAFs activity/epigenetic changes in CAFs | (89) |
Bonollo et al, 2020 | Increased stromal stiffness | (88) | |
Sejda et al, 2020 | Perineural invasion | (98) | |
March et al, 2021 | Neurotrophic growth factors | (99) | |
Senescence phenotype | Ewald et al, 2010 | Treatment resistance/therapy escape | (110) |
Wang et al, 2020 | Secretome sends tumorigenic signals to neighboring cells | (108) | |
Low visceral tropism | Beltran et al, 2016 | Additional mutations/CNA in critical genes | (37) |
Davies et al, 2020 | Neuroendocrine differentiation | (51) | |
Yegnasubramanian et al, 2008 | Epigenetic adaptation | (49) | |
Dormancy induction | Recasens et al, 2019 | Additional genetic aberrations | (148) |
Decker et al, 2017 | Beta-adrenergic signaling | (149) | |
Cackowski et al, 2017 | TYRO3, MERTK activity | (145) |
There are several factors that contribute to an indolent phenotype in subsets of prostate cancers. They include inherent properties of a tumor (such as slow proliferation rate, low visceral tropism), effects of treatment, immunosurveillance, TME-related effects, induction of dormancy/quiescence/senescence phenotype. However, as genetic and epigenetic alterations continue to accumulate, combined with the TME-endothelial compartment crosstalk, many tumors eventually escape dormancy and switch to aggressive disease.