Cellular senescence and cancer chemotherapy resistance

Abstract

Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. Importantly, clues to key resistance mechanisms may lie in the well-orchestrated and highly conserved cellular and systemic responses to injury and stress. Many anti-neoplastic therapies typically rely on DNA damage, which engages potent DNA damage response signaling pathways that culminate in apoptosis or growth arrest at checkpoints to allow for damage repair. However, an alternative cellular response, senescence, can also be initiated when challenged with these internal/external pressures and in ideal situations acts as a self-protecting mechanism. Senescence-induction therapies are an attractive concept in that they represent a normal, highly conserved and commonly invoked tumor-suppressing response to overwhelming genotoxic stress or oncogene activation. Yet, such approaches should ensure that senescence by-pass or senescence re-emergence does not occur, as emergent cells appear to have highly drug resistant phenotypes. Further, cell non-autonomous senescence responses may contribute to therapy-resistance in certain circumstances. Here we provide an overview of mechanisms by which cellular senescence plausibly contributes to therapy resistance and concepts by which senescence responses can be influenced to improve cancer treatment outcomes.

Introduction

Cancer is one of the most prevalent diseases diagnosed in developed countries and one of the leading causes of mortality in the United States. According to the National Cancer Institute approximately 1.6 million people were diagnosed with some form of cancer in 2010 and 570,000 lives were lost to neoplastic diseases (Howlader et al., 2011). Historically cancer was treated via surgical removal with some of the earliest indications of surgical intervention dating back to ancient Egypt with depictions of breast cancer surgeries (Mansfield, 1976). While surgical removal or radiotherapy of a solid tumor can be effective in treating localized primary disease, it has limited effectiveness in situations where tumor cells have spread outside of their tissue of origin.

The post-world war one era saw the dawning of systematic, scientifically based approaches for treating cancer patients. Experiments by Goodman and Gilman using nitrogen mustard for non-Hodgkin's lymphoma are representative of these early efforts that met with success. The evolution of systemic therapeutics and the science underlying their applications has resulted in complete cures for a subset of advanced tumor types and improved survival for most others. However, the ability of tumor cells to acquire resistance to cytotoxic and cytostatic agents can drastically reduce the efficacy of current interventions. It is interesting to note that the advent of chemotherapy was paralleled by the recognition of acquired therapy resistance (Chabner and Roberts, 2005). For patients with metastatic disease, drug resistance contributes to the majority of treatment failures (Longley and Johnston, 2005, Mahon et al., 2011). Despite initial responses, many tumors will relapse and progress regardless of repeated exposures to anti-neoplastic therapeutics. This naturally begs the question as to why? In this review we discuss the role of cellular senescence as a contributing factor in therapy resistance. We provide an overview of cellular damage responses to cancer treatments with a focus on signaling pathways leading to senescence, a state generally associated with tumor suppression. We describe evidence supporting contrary roles whereby senescence can enhance responses or promote resistance to cancer-directed therapeutics, and discuss opportunities to exploit senescence in the context of clinical care.