Fibroblast-mediated drug resistance in cancer

Abstract

Tumor progression relies upon the dynamic interaction of cancer cells with host fibroblasts, endothelial cells, immune cells and components of the extracellular matrix, collectively known as the tumor microenvironment. Despite this, relatively little is known about how normal host cells dictate the response of tumors to anti-cancer therapies. Emerging data suggests that host factors play a critical role in determining risks for tumor progression and decreased therapeutic responses. In particular, recent findings have provided evidence that the tumor microenvironment provides a protective niche that allows minor populations of cancer cells to escape from the cytotoxic effects of radiation, chemotherapy and targeted therapies. In this review we will outline the mechanisms by which tumor cells and host fibroblasts co-operate to drive tumor initiation and progression. In particular, we will focus upon the mechanisms by which tumor cells exposed to targeted therapies co-opt the host leading to therapeutic escape and resistance. We will end by discussing the idea that long-term responses to targeted anticancer therapies will only be achieved through strategies that target both the tumor and host.

Introduction

The initiation and progression of tumors is dependent upon the interaction of malignant cells with those of the host. This bi-directional communication is essential in providing support for the growing tumor and facilitates the processes that permit invasion, growth and tumor cell dissemination [1]. The past few years have seen major advances in the therapeutic management of advanced cancers through small molecule inhibitors that target key driver mutations [2]. This strategy, often termed targeted therapy has proven particularly successful in cancers that are “addicted” to the signaling activity of one oncogene. Examples where targeted therapy strategies have been used successfully include Bcr-Abl inhibitors in chronic myeloid leukemia (CML), KIT inhibitors in gastrointestinal stromal tumors (GIST) and EML4-ALK and EGFR inhibitors in non-small cell lung cancer (NSCLC) [2], [3], [4], [5], [6]. Melanoma is another deadly cancer for which targeted therapy is showing great promise. In a series of recent phase III clinical trials, good levels of tumor shrinkage were achieved when melanoma patients with activating mutations in the BRAF serine/threonine kinase were treated with small molecule inhibitors of BRAF (such as vemurafenib and dabrafenib) [7].

Although impressive anti-tumor responses are often observed in patients on targeted therapy most responses are short-lived and very few cures have been seen. It is clear that small molecule kinase inhibitors, especially when used in the single-agent setting, have a limited capacity to eradicate tumors. Although the full complexities of the adaptive mechanisms that facilitate therapeutic escape remain to be determined it is now becoming clear that the host is not a passive player in the process. In particular, signals from infiltrating stromal cell populations, such as carcinoma (or tumor)-associated fibroblasts (CAFs or TAFs), have been shown to provide critical survival signals that allow minor populations of cancer cells to evade therapy. It therefore seems likely that any curative combination therapeutic strategy will depend upon the dual targeting of the host and the tumor. In the following overview we will discuss the mechanisms by which recruitment and activation of host fibroblasts contributes to tumor progression and will outline some of the possible mechanisms by which the host contributes to drug resistance. It should be emphasized that fibroblasts are not the only mediators of host-derived of drug resistance, with important contributions arising from multiple other stromal cell types. A full discussion of these additional players is unfortunately beyond the scope of this manuscript.