Targeting the tumour stroma to improve cancer therapy

Abstract

Cancers are not composed merely of cancer cells alone; instead, they are complex 'ecosystems' comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote the resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistromal agents. Herein, we provide an overview of the advances in understanding the complex cancer cell-tumour stroma interactions and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.

Figure 1. Comparison of nonmalignant stroma and tumour strom

a. Nonmalignant epithelial tissue is supported by a stroma composed of extracellular matrix (ECM), fibroblasts, mesenchymal stromal cells (MSCs), osteoblasts (in bone), and/or chondrocytes (in joints). Cells in the nonmalignant stroma are usually in a quiescent state and maintain homeostasis in the ECM and epithelial compartment, in part by negatively regulating the proliferation, motility, and invasion of cells in the epithelial layer. When cancer develops, the stroma undergoes vast changes to become fibrotic and activated. The ECM becomes denser and more rigid, and is composed of alternative forms of connective fibres, such as tenascin and fibronectin, which cancer cells can invade through. Fibroblasts and MSCs change shape and expression profiles and become more proliferative and secrete higher levels of growth factors, cytokines, and chemokines (black arrows). Stromal fibroblasts in the tumour microenvironment are referred to as cancer-associated fibroblasts (CAFs) or myofibroblasts. The tumour stroma promotes cancer progression and metastasis, and leads to resistance to therapy and disease recurrence.

Figure 2. Tumour stroma-mediated chemoresistance

In response to anticancer therapy, the tumour stroma mediates resistance to therapy and disease recurrence. a | Dense fibrosis causes limited access of cancer cells to therapeutic agents in three ways: creating an extracellular matrix (ECM) barrier that such agents cannot diffuse through; promoting stromal cytochrome P450 (CYP)-mediated degradation of drugs; and increasing interstitial pressure that prevents therapeutic agents from entering the tumour. b | In response to chemotherapy or c | radiation therapy, cancer-associated fibroblasts (CAFs) and mesenchymal stromal cells (MSCs) secrete different growth factors, cytokines, and chemokines that promote cancer-cell survival, proliferation, invasion, and metastasis, leading to resistance. d | Targeted inhibition of a specific pathway (ligand–receptor X) results in the stromal secretion of new ligands (ligand–receptor Y), resulting in survival and resistance. e | In prostate cancer, decreased androgen receptor (AR) expression in the stroma leads to resistance to androgen-deprivation therapies. In breast cancer; the stroma promotes decreased oestrogen receptor (ER) expression in cancer cells, leading to resistance to antihormonal therapies. f | CAFs, MSCs, and ECM suppress effector immune cell activation and tumour infiltration.

Figure 3. Targeting tumour stromal cells in addition to cancer cells

a | Currently, most antitumour therapies target and eliminate cancer cells, and are not design to directly affect the tumour stroma. b | However, tumour recurrence can result from the interactions of the tumour stroma with both cancer cells and anticancer therapies. Through its interaction with cancer cells, the stroma promotes the hallmarks of cancer and can induce a therapy-resistant phenotype. Through its direct interaction with anticancer therapy, the stroma can prevent the action of such therapies on cancer cells. (FIG. 2). c | We posit that, in addition to targeting cancer cells, anticancer therapeutic strategies should include methods to target and constrain the stroma, or to revert it to a tumour-suppressive state.