Table 2.
Tumor microenvironment factors reported with cisplatin resistance.
| Factor | Action mechanism | Experimental result | Reference |
|---|---|---|---|
| Physical | |||
| Physical barriers | Limit penetration of CDDP into tumors | Decreased CDDP accumulation in tumor cells | [62,63] |
| Fluidic shear stress | Activation of PI3K/Akt signaling and ABC drug transporters | Cancer stemness progression and CDDP resistance induced by fluidic shear stress | [64] |
| ECM | 1. Limited CDDP diffusion 2. The activation of survival signals through the interaction with tumor cells |
Increased cancer cell sensitivity to CDDP in collagen- and fibronectin-deficient ECMs | [65] |
| Biological | |||
| Hypoxia | Increased cancer cell stemness and multidrug transporter expression | Increased CDDP resistance in low oxygen levels | [66,67,68,69,70] |
| Acidity | Increased multidrug transporter expression | Increased CDDP resistance in acidic conditions | [71,72] |
| CAF | 1. CAF-secreted growth factors or cytokines affecting cell apoptosis or intrinsic drug resistance 2. Metabolism of CAFs regulated by effector T-cells |
1. Increased CDDP resistance by CAF-secreted cytokines such as IL-6, IL-8, IL-11, insulin-like growth factor 1, and TGF-β 2. CAFs-mediated GSH metabolism and platinum resistance abrogated by cytotoxic T cells |
[73,74,75,76,77,78] |
| TAM | Secretion of cytokines by TAM in an M2 polarization state | Increased CDDP resistance by TAM-secreted cytokines such as IL-6 and type I interferon | [79,80] |
CDDP: cisplatin, PI3K: phosphatidylinositol 3-kinase, ABC: ATP-binding cassette transporter, ECM: extracellular matrix, CAF: carcinoma-associated fibroblast, TAM: tumor-associated macrophage, IL: interleukin, TGF: transforming growth factor, GSH: glutathione.