Tumor stroma as targets for cancer therapy

Abstract

Cancer is not only composed malignant epithelial component but also stromal components such as fibroblasts, endothelial cells, and inflammatory cells, by which an appropriate tumor microenvironment (TME) is formed to promote tumorigenesis, progression, and metastasis. As the most abundant component in the TME, cancer-associated fibroblasts (CAFs) are involved in multifaceted mechanistic details including remodeling the extracellular matrix, suppressing immune responses, and secreting growth factors and cytokines that mediate signaling pathways to extensively affect tumor cell growth and invasiveness, differentiation, angiogenesis, and chronic inflammatory milieu. Today, more and more therapeutic strategies are purposefully designed to target the TME as well as tumor cells. This review will focus on the role of CAFs in tumor development and the novel strategies to target this component to inhibit the tumor growth.

Introduction

Despite continued development of surgical techniques and meticulously designed chemotherapy or radiotherapy regimens, cancer remains the second leading cause of deaths after cardiovascular disease. The American Cancer Society estimates that in 2012, cancer will affect more than 1,600,000 patients and result in nearly 580,000 deaths (Siegel et al., 2012). Cancer has long been believed to be a cell-autonomous process, in which consecutive mutations in oncogenes and tumor suppressors lead to infinite tumor cell proliferation (Kenny et al., 2007). Understandably, most research focuses on these tumor cells. However, mounting evidence suggests that tumor genesis and progression are determined not only by tumor cells, but also by a favorable tumor microenvironment (TME) (Hu et al., 2009, Tyan et al., 2011), which supports the “seed [tumor cells] and soil [tumor stroma]” hypothesis proposed by Paget more than 100 years ago (Paget, 1989).

Tumor is considered a complicated “organ” with dysregulated growth (Bissell & Radisky, 2001) that consists of a highly heterogeneous population of cell including tumor cells, fibroblasts, inflammatory cells (e.g., lymphocytes and macrophages), endothelial cells, pericytes, and smooth muscle cells. Existing data clearly reveal that the TME differs distinctly from the corresponding normal stroma (Fig. 1). Rather than a “bystander”, the TME acts as an important “accomplice” of tumorigenesis and development.

Evidence suggests that there is close link between tumor cells and their TME: the basement membrane (BM) is degraded and the extracellular matrix (ECM) is overproduced; epithelial to mesenchymal transition (EMT) may occur; activated fibroblasts and inflammatory cells release plentiful growth factors, cytokines, and ECM-degrading proteases; newly formed vasculatures provide nutritional support to tumor cells (Petersen et al., 2003, Radisky and Radisky, 2007). All of the above changes in turn act on tumor cells and stroma to further alter and facilitate tumor progression and metastasis (Stuelten et al., 2010). On the basis of these data, it has been suggested that targeting the TME is a promising therapeutic approaches for diverse tumor types and disease stages (Chuaysri et al., 2009). The targets are also rapidly expanding from endothelial cells to other stromal components including fibroblasts, inflammatory cells, and the ECM.

In this review, we focus in particular on the role of the major cellular component in tumor milieu, cancer-associated fibroblasts (CAFs). We then discuss several crucial signaling pathways between the tumor and CAFs. Finally, we highlight the current advances in the development of novel therapeutic strategies against CAFs. Alone or in combination with conventional therapies, some target agents have been approved by Food and Drug Administration (FDA), but many more are currently being explored.