Macrophages and Fibroblasts, Key Players in Cancer Chemoresistance

Abstract

Chemotherapy is routinely used in cancer treatment to eliminate primary and metastatic tumor cells. However, tumors often display or develop resistance to chemotherapy. Mechanisms of chemoresistance can be either tumor cell autonomous or mediated by the tumor surrounding non-malignant cells, also known as stromal cells, which include fibroblasts, immune cells, and cells from the vasculature. Therapies targeting cancer cells have shown limited effectiveness in tumors characterized by a rich tumor stroma. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are the most abundant non-cancerous cells in the tumor stroma and have emerged as key players in cancer progression, metastasis and resistance to therapies. This review describes the recent advances in our understanding of how CAFs and TAMs confer chemoresistance to tumor cells and discusses the therapeutic opportunities of combining anti-tumor with anti-stromal therapies. The continued elucidation of the mechanisms by which TAMs and CAFs mediate resistance to therapies will allow the development of improved combination treatments for cancer patients.

Keywords: chemoresistance; fibroblasts; macrophages; therapy resistance; tumor microenvironment; tumor stroma.

FIGURE 1

Macrophage polarization. Bone marrow derived monocytes or tissue derived monocytes can be polarized toward either an M1 or M2 phenotype. Classical activation toward M1 polarization occurs in response to interferon gamma (IFNγ) and lipopolysaccharide (LPS) leading to a Th1 response associated with bacteria and viruses as well as possessing anti-tumorigenic properties. Alternative activation toward an M2 phenotype is triggered in response to toll-like receptors (TLRs), immune complexes, IL-4, IL-13, IL-10, and glucocorticoids. M2 macrophages lead to a Th2 response and exhibit anti-parasitic behavior. In cancer, M2-like macrophages promote tumor progression.

FIGURE 2

Fibroblast activation. Quiescent fibroblasts produce few extracellular matrix (ECM) components such as fibronectin and collagen type 1 (Col1a1). They express fibroblasts specific protein-1 (FSP-1), actin and vimentin and secrete pigment epithelium-derived factor (PEDF) and thrombospondin-2 (THBS2). When stimulated with transforming growth factor beta (TGF-β), reactive oxygen species (ROS) or hypoxia, quiescent cells become activated increasing their contractility, proliferation and secretion. Activated myofibroblasts produce larger volumes of fibronectin and collagen along with tenascin-c and secreted protein acidic and rich in cysteine (SPARC). Increased secretion includes IL-6, tissue inhibitor of metalloproteinase (TIMPs), TGF-β, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and CXCL10. Upregulated receptors/markers include alpha smooth muscle actin (αSMA), platelet derived growth factor receptor alpha/beta (PDGFRα/β), fibroblast activation protein (FAP), discoidin domain-containing receptor 2 (DDR2), desmin, and vimentin.

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).

FIGURE 4

Therapeutic strategies to overcome chemoresistance mediated by TAMs and CAFs. CAFs: Reprogramming activated CAFs back toward a quiescent phenotype by anti-Smoothened (Smo), anti-sonic hedgehog (Shh), all-trans retinoic acid and calcipotriol (vitamin D analog) while fibroblast growth factor 2 (FGF2) targeting agents prevents resistance of tumor cells to anti-estrogens in breast cancer. TAMs: Repolarizing M2 macrophages back to an M1-like phenotype can be mediated by a CD40 agonist. Prevention of macrophage recruitment to tumor sites is currently being achieved by targeting the colony-stimulating factor 1 (CSF-1) and C-C motif chemokine 2 (CCL2) signaling axis. Anti-angiopoietin-2 (Ang-2) antibodies prevent TAM interaction with blood vessels. IL-10 produced by TAMs promotes chemoresistance which can be abrogated by treatment with anti-IL-10 antibodies. TAMs and CAFs secrete insulin-like growth factor 1 and 2 (IGF1 and IGF2) which makes pancreatic and breast tumors chemoresistant and more metastatic. Treatment of tumors with anti-IGF blocking antibodies increases the response of pancreatic and breast tumors to chemotherapy and decreases tumor growth and metastasis.