Review
Hallmarks of cancer: Interactions with the tumor stroma

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Abstract

Ten years ago, Hanahan and Weinberg delineated six “Hallmarks of cancer” which summarize several decades of intense cancer research. However, tumor cells do not act in isolation, but rather subsist in a rich microenvironment provided by resident fibroblasts, endothelial cells, pericytes, leukocytes, and extra-cellular matrix. It is increasingly appreciated that the tumor stroma is an integral part of cancer initiation, growth and progression. The stromal elements of tumors hold prognostic, as well as response-predictive, information, and abundant targeting opportunities within the tumor microenvironment are continually identified. Herein we review the current understanding of tumor cell interactions with the tumor stroma with a particular focus on cancer-associated fibroblasts and pericytes. Moreover, we discuss emerging fields of research which need to be further explored in order to fulfil the promise of stroma-targeted therapies for cancer.

Introduction

Tumors arise from normal cells through genetic alterations affecting the tightly controlled systems for growth control. Ten years ago, Hanahan and Weinberg enumerated six hallmarks of cancer that are essential for a cell to acquire on its way to any of the more than one hundred different types of human malignancies [1]. The specification of the traits of a tumor cell is the distillate of several decades of research dedicated to the malignant cell. However, the tumor cell-centric view of cancer does not take into account the context in which malignant cells subsist. As the cancer progresses, the surrounding microenvironment co-evolves into an activated state through continuous paracrine communication, thus creating a dynamic signaling circuitry that promotes cancer initiation and growth, and ultimately leads to a fatal disease. Indeed, many of the hallmarks of cancer delineated by Hanahan and Weinberg are provided by various stromal components, including endothelial cells, pericytes, fibroblasts, various classes of leukocytes, and extra-cellular matrix (Fig. 1). Herein, we review the pro-tumorigenic actions of tumor-associated mesenchymal cell types, i.e. cancer-associated fibroblasts (CAFs) and pericytes, in the context of the original hallmarks of cancer. Additionally, we discuss potential targeting opportunities for the development of drugs aimed at the tumor stroma, as well as delineate emerging areas of research.

Section snippets

Cancer-associated fibroblasts

The cancer-associated fibroblast is the most prominent cell type within the tumor stroma of many cancers, most notably breast and pancreatic carcinoma (Fig. 1) [2], [3]. Recent studies highlight several different subpopulations of stromal fibroblasts within tumors designated by only partly overlapping marker expression, including α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF) receptors, and fibroblast specific protein (FSP)-1 [4], [5]. The heterogeneity in marker expression

Pericytes

Pericytes are contractile cells in close physical contact with endothelial cells in capillaries and venules (Fig. 1). In quiescent tissues, pericytes readily express markers such as PDGF receptor-β, NG2 and desmin, while lacking expression of α-SMA. However, tumor pericytes are characterized by a more loosely attached phenotype with a disparate pattern of marker expression, including α-SMA [9]. A range of signaling pathways, including PDGF, transforming growth factor (TGF)-β, angiopoietin and

Self-sufficiency in growth signals

CAFs directly stimulate tumor cell proliferation through provision of various growth factors, hormones and cytokines in a context-dependent manner. Prototypical epithelial mitogens, such as hepatocyte growth factor (HGF), and members of the epidermal growth factor, fibroblast growth factor (FGF) and Wnt families, as well as cytokines such as stromal-derived factor (SDF)-1α (CXCL12) and IL-6, are all highly expressed by CAFs in different tumor types [13]. Intriguingly, many of these factors

CAF- and pericyte-mediated resistance to therapy

Given the wealth of stroma-derived factors aiding in cancer initiation, growth and progression, the stromal compartment is likely to influence therapeutic outcome, as well as provide ample opportunities for targeting. Indeed, a stroma-derived gene expression signature prognostic of clinical outcome was described for breast carcinoma [37]. Further evidence for the notion that CAFs determine therapeutic outcome in breast cancer patients comes from elucidation of a CAF gene signature predictive

Towards an improved CAF and pericyte taxonomy

It is becoming well recognized that CAFs within individual tumors display heterogeneity, and that the dominating CAF phenotypes also differ within and between histological tumor types. Clinical significance of these variations is suggested by many recent studies demonstrating prognostic or response-predictive significance of CAF-derived gene-expression profiles or markers, such as the PDGF receptor-β, SPARC or α-SMA [37], [38], [49], [50], [51]. Identification of biologically relevant CAF

Concluding remarks

Taken together, CAFs and pericytes are increasingly recognized as integral parts of the tumorigenic process. Conceivably, studies in this area will be most productive if they manage to integrate tissue culture studies, analyses in animal models and characterization of human tissue material representing early stages of cancer. Given the multitude of cellular interactions already described, the prospects for development of novel anti-cancer therapies or preventive strategies based on an

Acknowledgments

KP is supported by a Young Investigator Award by the Swedish Cancer Society, as well as by grants from the Karolinska Institutet Cancer network, the Swedish Childhood Cancer Foundation, and Jeansson's Foundation. AÖ is supported by Swedish Cancer Society, “Cancerföreningen i Stockholm” and “Konung Gustaf V:s Jubileumsfond “. Finally, KP and AÖ acknowledge generous support in the form of a Linnaeus grant from the Swedish Research Council to the STARGET consortium (//ki.se/ki/jsp/polopoly.jsp?d=22000&l=en

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