Elsevier

Drug Resistance Updates

Volume 19, March 2015, Pages 33-42
Drug Resistance Updates

Host effects contributing to cancer therapy resistance

https://doi.org/10.1016/j.drup.2014.12.002Get rights and content

Abstract

There are several approaches for the management of malignant disease. However, tumor resistance to therapy is still a major challenge in the clinic. Efflux transporters, genetic responses and enzyme activity in tumor cells are examples of the main modalities that account for resistance to therapy. In addition, emerging evidence suggests that the host also plays a significant role in promoting therapy resistance. Recruitment of different host cell types to the treated tumor site occurs in response to a range of therapies, including chemotherapy, radiation and even targeted drugs. This host response may have a protective effect on the tumor cells, not only negating anti-tumor activity, but also promoting a resistant tumor. In this review, we focus on host–tumor interactions leading to therapy resistance with special emphasis on different host cells and secreted factors within the tumor microenvironment. The development of novel inhibitors that block the host response to therapy could be used as a treatment strategy to enhance therapy outcomes and survival.

Introduction

Tumor initiation, growth and expansion are dependent on several specific intrinsic tumor cell characteristics, such as an endless proliferation state, sensitivity to growth factors, and the ability to escape from apoptotic pathways. In addition, the tumor microenvironment has also been shown to play an important role in promoting tumor growth and spread to distant sites (Hanahan and Weinberg, 2000). For example, angiogenesis, which allows a flow of nutrients and oxygen to the tumor and removes tumor metabolic waste, is an essential process for tumor cell proliferation and spread (Folkman, 2003). Angiogenesis is achieved by the proliferation of local endothelial cells that form sprouting vessels to tumors, and also by several bone marrow derived cell (BMDC) types that are recruited into the neoplastic lesion and promote vessel formation (Patenaude et al., 2010, Kovacic and Boehm, 2009, Lamagna and Bergers, 2006). Another example for the contribution of host cells to tumor growth is related to the immune system. While tumors seem to have the ability to evade the immune system by inhibiting their mechanism of cell killing, a significant number of immune cells still infiltrate growing tumors. They include macrophages, lymphocytes, dendritic cells, and natural killer cells (NKs) which contribute to tumor growth or suppress it by various mechanisms. Myeloid-derived suppressor cells (MDSCs), for example, home in large numbers to the tumor site, and negatively regulate the immune cells which are active against tumor cells (Cavallo et al., 2011). Therefore, it is currently clear that the cross-talk between tumor cells and cells in the microenvironment highlight the diversity of functions different cell types have against and in favor of tumor.

The therapeutic management of cancer involves several approaches including chemotherapy, targeted treatment and radiotherapy used separately or simultaneously. Such treatments can efficiently kill cancer cells due to their ability to target rapidly proliferating cells and promote tumor cell death by various mechanisms. However, cancer cells have emerged ways to protect themselves from the majority of treatments thus making them resistant to therapy.

In general, insensitivity of tumors to a variety of anticancer drugs is known as multidrug resistance (MDR) involving inactivation or elimination of the drug from the target tumor cells. Overexpression of efflux transport proteins such as ABC transporters, and alterations in drug targets, enzymatic activity and genetic response have been described as processes leading to therapy resistance. These processes involve direct changes within the tumor cells which may occur before or during therapy (Higgins, 1992, Gottesman et al., 2002, Holohan et al., 2013). For example, antifolate resistance is known to be induced by alterations in influx and efflux transporters and in folate dependent enzymes (Gonen and Assaraf, 2012). Therefore, targeting folate receptor overexpressed in solid tumors is a novel evolving cancer treatment (Assaraf et al., 2014).

Kim and Tannock provided an explanation for relapse or tumor resistance that occurs following an initial response to therapy. They postulated that at the time of the drug-free break periods between consecutive bolus acute chemotherapy treatments, tumor cells repopulate the tumor site and contribute to tumor regrowth at an accelerated cell proliferation rate (Kim and Tannock, 2005). Several mechanisms explaining this phenomenon have been suggested in the last few years, some of which are related to different cell types that are recruited to the tumor microenvironment after therapy.

In this review, we discuss collective studies describing how anti-cancer therapies induce a host response that, in turn, directly affects various tumor characteristics, eventually leading to therapy resistance (Fig. 1). We describe the role of different types of host cells and host-secreted factors, and discuss new possible treatment modalities based on targeting the host response.

Section snippets

Host cells promoting drug resistance

It has become clear that cancer cells clustered together as a solid tumor are able to recruit different cell types to the tumor bed. Bone marrow derived cells, such as mesenchymal stem cells (MSCs), hematopoietic cells and circulating endothelial progenitor cells (CEPs), have been shown to be recruited to the tumor site, and together with adipocytes, astrocytes and fibroblasts, they constitute the tumor microenvironment. Crosstalk between tumor cells and the different cell types in the tumor

Host factors promoting drug resistance

Factors that are secreted by the host in response to therapy may protect tumor cells from therapy or recruit host cells that promote tumor cell survival mechanisms. Here, we provide examples of resistance-inducing host factors that are secreted in response to several treatment modalities, including cytotoxic agents, radiation, and targeted drugs.

Preventing host driven drug resistance

Many efforts have been made to develop approaches to overcome resistance to anti-cancer treatments. Much of the resources in this direction are related to directly sensitizing tumor cells to the therapy. This includes modulation of ABC transporters (Krishna and Mayer, 2000) and inducing drug delivery systems (Patil and Panyam, 2009, Lee et al., 2008, Nemunaitis et al., 2005, Livney and Assaraf, 2013). However, here we outline several approaches that rely on blocking host effects following

Conclusions

The tumor microenvironment is a crucial and essential element participating in the response to a wide range of cancer treatments. While tumor cells have been the main focus in the field of therapy resistance, emerging evidence points to the significant contribution of host cells. While anti-cancer treatments are usually beneficial, they can also act detrimentally, altering the biological behavior of the disease in unwanted ways (Fig. 2). Hence, the apparent benefit of anti-cancer treatments

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

This review was supported in part by grants from the European Research Council (under FP-7 program, 260633), Israel Science Foundation (490/12), Israel Cancer Research Fund (708/12), and Rappaport funds given to YS. OBK is supported by a grant from the Slava Smolokowski Fund to the Rambam-Atidim Academic Excellence Program.

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