FIGURE 3.

Mechanisms of chemoresistance mediated by TAMs and CAFs. (A) Cancer cells attract TAMs via CSF-1. TAMs confer resistance of MCF-7 breast cancer cells toward cyclophosphamide, methotrexate and 5-fluorouracil (5-FU; Paulus et al., 2006). (B) Cathepsins B and S secreted by TAMS mediate resistance of breast cancer cells to taxol in MMTV-PyMT mouse model (Shree et al., 2011). (C) In the MMTV-PyMT transgenic mouse model, cancer cell necrosis caused by doxorubicin treatment causes cancer cells to release the monocyte chemoattractant CCL2. Recruited TAMs produce MMP-9 which causes leakiness of blood vessels and reduction in doxorubicin delivery (Nakasone et al., 2012). (D) In PDAC, CAFs increase deposition of hyaluronan (HA) creating an increase in fluid retention and subsequently interstitial pressure in the tumor rises causing the collapse of blood vessels and limiting the delivery of chemotherapeutic agents (DuFort et al., 2016). (E) CAF secreted IL-6 stimulates the upregulation of CXCR7 through STAT3/NF-kB signaling promoting resistance of esophageal squamous cell carcinoma cells against cisplatin and 5-FU (Qiao et al., 2018). (F) CAF-derived TGF-β upregulates FOXO1 expression in esophageal squamous cell carcinoma cells triggering reciprocal TGF-β secretion which in turn increases the levels of αSMA expression in CAFs and resistance to cisplatin, taxol, irinotecan (CPT-11), 5-FU, carboplatin, docetaxel, pharmorubicin, and vincristine (Zhang et al., 2017). (G) TAM and CAF derived IGF-1 and IGF-2 activate insulin and IGF-1 receptor signaling on tumor cells conferring resistance of pancreatic and breast tumors to gemcitabine and paclitaxel (Ireland et al., 2016, 2018).