Cellular senescence and cancer chemotherapy resistance
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.
Section snippets
Chemotherapeutics, cellular damage and damage responses
Pharmacological agents designed to induce tumor cell death and/or suppress growth fall into several classes based on mechanism of action. Whereas recent advances in anti-cancer therapeutics have focused on developing inhibitors that exploit specific oncogenic mutations that hyper-activate growth regulatory pathways, the most widely used agents are poorly selective for neoplastic cells and rely on marginal differences between benign cells and tumor cells that involve proliferation rates, DNA
The DNA Damage Response
The DNA Damage Response (DDR) is a complex developmentally conserved process which is initiated following injury to the integrity of DNA. This response is set in motion to protect cells from irreversible damage following exposure to exogenous/endogenous genotoxins, and to eliminate those cells with damage too extreme to repair fully. There are several factors that can induce the damage response ranging from UV exposure to commonly used cancer treatments such as γ-radiation and chemotherapeutics
Cellular senescence: mechanisms and outcomes
The word senescence is derived from the Latin word senex, meaning old age or advanced in age. In addition to describing an organismal state that is associated with advanced chronological age, the term senescence has also been applied to a phenotype observed in individual cells, also associated with chronological age—often measured by numbers of cell divisions. Cellular senescence is also influenced by other factors that modify DNA and the functions of other organelles to phenocopy the
The Pro: promoting tumor senescence to overcome drug resistance
It is important to recognize that divergent views exist regarding the dynamics of senescence in the clinical setting, and the ramifications of senescence as a desirable or adverse contributor to therapeutic responses. There have been an increasing number of reports indicating that initiating a senescence program in solid tumors could be a potential therapeutic treatment to overcome drug resistance. This is based on the idea that tumor cells remain prone to senescence and that they are readily
The Con: senescence and the tumor microenvironment promote resistance
The importance of the microenvironment and its role in therapy response is increasingly recognized. A patient treated with cytotoxic agents receives systemic damage impacting normal constituents of tissue and organ systems as well as the neoplastic cells. The resulting damage may elicit a response from the tumor microenvironment (TME) which potentially can have a dramatic impact upon treatment efficacy. Several studies have documented that the DDR induces a remarkable spectrum of secreted
Therapy resistance and breaking senescence
While senescence is generally considered an irreversible state of cellular arrest, the potential dangers of an emergent phenotype should be considered. If cells in the arrested state are not cleared via processes such as phagocytosis they remain in the organism harboring the potential to recapture the proliferative state, often with damaged genomes. There have been reports both supporting immune mediated attrition (Xue et al., 2007) and the continued accretion of senescent cells in vivo (Dimri
Conclusions and future directions
Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. In this context, manipulating cellular senescence may improve therapy responses via several mechanisms. The promotion of ‘intrinsic’ tumor cell senescence is an attractive concept in that it represents a normal, highly conserved and commonly invoked tumor-suppressing response to overwhelming genotoxic stress or
Acknowledgment
This work was supported by NIH grants P50CA097186, U54CA126540 and U01CA164188.
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