Cell Death–Stimulated Cell Proliferation: A Tissue Regeneration Mechanism Usurped by Tumors During Radiotherapy
Introduction
Death is the fate for all cells in every living organism. Although this is a universal truth, death can take many forms. A plethora of new terms, particularly in the last 3 decades, have emerged to describe the various modes of cell death.1 Cell death plays a central role in cancer research because it is the key in both cancer etiology and cancer therapy. During carcinogenesis, normal cells have to evade cell death signals to become tumorigenic. In cancer therapy, the ultimate goal is to achieve the death of all cancer cells in the patient's body. Although the goal of killing cancer cells through radiation is very straightforward, there is increasing recognition that cell death and tumor repopulation, which is the opposite process of tumor cell loss caused by treatment, are closely intertwined. It appears that compensatory proliferation, a process initially identified in lower organisms during the regeneration of lost tissue,2, 3 is an evolutionarily conserved process that also functions in mammals. Moreover, tumors appear to have usurped this mechanism to their own advantage when dealing with cytotoxic cancer therapy. In this review, we attempt to summarize some recent advances in our understanding of the dynamic interactions between cell death and tumor repopulation; repopulation is a major reason for treatment failure during radiotherapy. We start by reviewing some of the basic concepts of different modes of cell death. We then review the phenomenon of compensatory proliferation during tissue regeneration in lower organisms. We also take survey of recent literature on cell death–induced tissue regeneration and wound healing in mammalian organisms. Finally, we examine results concerning the roles of apoptosis in tumor cell repopulation during radiotherapy and its potential implications for drug development and radiotherapy.
Section snippets
Cell Death: The Current Paradigm
Broadly speaking, there are 3 distinct modes of cell death: necrosis, apoptosis, and autophagy. Although all 3 pathways can achieve the simple end point, death of the cell, the molecular signaling cascades and consequences to the host can be highly varied. For example, necrosis is often accompanied by an inflammatory response, which can promote tumor development; however, the concomitant release of tumor antigens can also lead to an enhanced immune response through activation of immature
Compensatory Proliferation, Cell Death–Induced Tissue Regeneration in Lower Organisms
Apoptosis is generally thought of as a means for multicellular organisms to get rid of damaged or unwanted cells. However, in recent years it was shown that apoptosis often plays key facilitative roles in tissue regeneration. This phenomenon, which was termed compensatory proliferation, was first observed in lower organisms, such as planaria, hydra, and drosophila. Planarians, which are simple worms, exhibit remarkable regenerative capabilities and can form complete individuals from the
Cell Death–Stimulated Skin Wound Healing and Liver Regeneration
As we have learned from observations made in lower organisms, increasing cell death in one cell population can inadvertently stimulate accelerated proliferation of surviving cells. Evolutionarily conserved aspects of this kind of signaling may very well be present in higher organisms for the purpose of wound healing and tissue regeneration. For example, just as the JNK pathway has been shown to play a role in drosophila imaginal disc compensatory proliferation, JNK activation may also play a
Cell Death Mechanisms and Radiotherapy
Radiation therapy is a standard practice in the treatment of cancer with more than 50% of patients receiving it at some point during their illness.52 Ionizing radiation exerts its anticancer effect by reacting with molecular oxygen and water to generate reactive oxygen species that can attack deoxyribose in the DNA backbone leading to double strand breaks.53 Sublethal doses of radiation can trigger a nuclear DNA damage response; however, when the extent of damage becomes too much to repair,
Tumor Repopulation, A Key Issue in Radiation Biology and Therapy
Accelerated tumor repopulation after radiation therapy is not a new concept63, 64, 65, 66, 67 and has been noted following chemotherapy as well.68, 69, 70 Early studies carried out by Rodney Withers et al.63, 71 in both mice and later in human clinical trials detailed the occurrence of accelerated tumor repopulation after treatments with ionizing radiation and pioneered the work on modifying radiation treatment regimens to circumvent this effect.72, 73 It was discovered that in certain cell
Cell Death–Stimulated Tumor Repopulation During Radiotherapy
Aberrant apoptosis is considered a hallmark of cancer, and activation of caspases to induce apoptosis is the prevailing ideology in most cancer treatments.26, 27, 84, 85, 86 However, recent results from our laboratory demonstrated that this model may be oversimplified.
Building on our results on proregeneration properties of caspases-3 and -7, we discovered an important role for caspase-3 in tumor cell repopulation during radiotherapy.87 We found that irradiated caspase-3-deficient MEF (Casp3−/−
Summary
Recent discoveries on the roles of apoptotic caspases in tissue regeneration and in tumor cell repopulation are both surprising and exciting. For cancer therapy, there could be tremendous implications. Efforts to develop agents that activate caspases must now be re-examined. On the contrary, small molecule inhibitors of caspases should now be evaluated for their properties to enhance cancer radiotherapy or chemotherapy. Although human clinical trials are lacking in this area, several studies
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2019, Acta BiomaterialiaCitation Excerpt :Although cytotoxic chemotherapeutics kill cancer cells, cancer recurrence nearly inevitably occurs [40]. Increasing evidence has suggested that cancer recurrence after chemotherapy is partially attributed to caspase-exacerbated repopulation of residual cancer cells [42]. Our group and other groups have provided preliminary results showing that caspase-3-dependent cleavage of iPLA2 during chemotherapy triggers the activation of the AA metabolic pathway in breast and ovarian cancers [13,22].
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2019, Mathematical BiosciencesCitation Excerpt :Examples are found in epithelial wound repair and tissue regeneration in model animals such as mice, Drosophila, Hydra, Planaria, and Xenopus [8–10]. Such a phenomenon, cell death-induced proliferation (CDIP), has been observed even in tumorigenic cells [9,11]. For example, it was reported in studies on mice that cell death arising in normal liver tissues promotes proliferation of neighboring normal cells and at the same time activates tumor formation [12,13].
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2019, Journal of Theoretical BiologyCitation Excerpt :In both lymphoma and prostate cancer, loss of part of the tumor cells through induction of apoptosis can promote tumor growth (Ford et al., 2015; Roca et al., 2018). It has been hypothesized that tumor cell repopulation is mediated by compensatory proliferation (Zimmerman et al., 2013). This process is usually activated after loss of tissue during regeneration, most markedly in anamniote vertebrates, and involves a precise temporal orchestration of apoptosis of injured cells, removal of cellular debris through phagocytosis by macrophages, and mitosis of stem and progenitor cells (Sîrbulescu and Zupanc, 2011; Sîrbulescu and Zupanc, 2013; Zupanc and Sîrbulescu, 2013).
Naturally occurring compounds in differentiation based therapy of cancer
2018, Biotechnology AdvancesCitation Excerpt :While “find me”, “eat me”, “keep out inflammation” represents connected cascades of events leading to apoptotic cell clearance, the “be loyal” signal is evoked in initial phase of apoptosis prior to or even independently of completion of the apoptotic process (Fan and Bergmann, 2008). Several examples exist indicating that compensatory proliferation might play a role in the conventional therapeutic failures in advanced cancers (reviewed in Zimmerman et al., 2013). The better understanding of the background of the tumor expansion as the consequence of aggressive treatment requires the proper comprehension of the relation occurring between cell death and proliferation in tumor tissue.
The authors declare no conflict of interest.