Cell Death–Stimulated Cell Proliferation: A Tissue Regeneration Mechanism Usurped by Tumors During Radiotherapy

https://doi.org/10.1016/j.semradonc.2013.05.003Get rights and content

The death of all the cancer cells in a tumor is the ultimate goal of cancer therapy. Therefore, much of the current effort in cancer research is focused on activating cellular machinery that facilitates cell death such as factors involved in causing apoptosis. However, recently, a number of studies point to some counterintuitive roles for apoptotic caspases in radiation therapy as well as in tissue regeneration. It appears that a major function of apoptotic caspases is to facilitate tissue regeneration and tumor cell repopulation during cancer therapy. Because tumor cell repopulation has been shown to be important for local tumor relapse, understanding the molecular mechanisms behind tumor repopulation would be important to enhance cancer radiotherapy. In this review, we discuss our current knowledge of these potentially paradigm-changing phenomena and mechanisms in various organisms and their implications on the development of novel cancer therapeutics and strategies.

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

References (98)

  • J.S. Hwang et al.

    Detection of apoptosis during planarian regeneration by the expression of apoptosis-related genes and TUNEL assay

    Gene

    (2004)
  • S. Chera et al.

    Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration

    Dev Cell

    (2009)
  • B. Galliot et al.

    The Hydra model: Disclosing an apoptosis-driven generator of Wnt-based regeneration

    Trends Cell Biol

    (2010)
  • H.D. Ryoo et al.

    Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways

    Dev Cell

    (2004)
  • J.R. Huh et al.

    Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role

    Curr Biol

    (2004)
  • Y. Fan et al.

    Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye

    Dev Cell

    (2008)
  • R.F. Schwabe et al.

    c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration

    Hepatology

    (2003)
  • S. Maeda et al.

    IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis

    Cell

    (2005)
  • G. Atsumi et al.

    Fas-induced arachidonic acid release is mediated by Ca2+-independent phospholipase A2 but not cytosolic phospholipase A2, which undergoes proteolytic inactivation

    J Biol Chem

    (1998)
  • K. Lauber et al.

    Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal

    Cell

    (2003)
  • X. Zhao et al.

    Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells

    J Biol Chem

    (2006)
  • J.F. Ward

    DNA damage produced by ionizing radiation in mammalian cells: Identities, mechanisms of formation, and reparability

    Prog Nucleic Acid Res Mol Biol

    (1988)
  • W.C. Dewey et al.

    Radiation-induced apoptosis: Relevance to radiotherapy

    Int J Radiat Oncol Biol Phys

    (1995)
  • K.R. Trott

    Cell repopulation and overall treatment time

    Int J Radiat Oncol Biol Phys

    (1990)
  • L.B. Marks et al.

    Accelerated repopulation: Friend or foe? Exploiting changes in tumor growth characteristics to improve the “efficiency” of radiotherapy

    Int J Radiat Oncol Biol Phys

    (1991)
  • B. Maciejewski et al.

    Dose fractionation and tumour repopulation in radiotherapy for bladder cancer

    Radiother Oncol

    (1991)
  • A.J. Davis et al.

    Repopulation of tumour cells between cycles of chemotherapy: A neglected factor

    Lancet Oncol

    (2000)
  • L.J. Peters et al.

    Applying radiobiological principles to combined modality treatment of head and neck cancer—The time factor

    Int J Radiat Oncol Biol Phys

    (1997)
  • A.C. Begg et al.

    Tumour cell repopulation during fractionated radiotherapy: Correlation between flow cytometric and radiobiological data in three murine tumours

    Eur J Cancer

    (1991)
  • Z. Huang et al.

    Onset time of tumor repopulation for cervical cancer: First evidence from clinical data

    Int J Radiat Oncol Biol Phys

    (2012)
  • R. Suwinski et al.

    Rapid growth of microscopic rectal cancer as a determinant of response to preoperative radiation therapy

    Int J Radiat Oncol Biol Phys

    (1998)
  • J.Z. Wang et al.

    Impact of tumor repopulation on radiotherapy planning

    Int J Radiat Oncol Biol Phys

    (2005)
  • D.H. Nguyen et al.

    Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type

    Cancer Cell

    (2011)
  • J. Shao et al.

    Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer

    J Biol Chem

    (2005)
  • W. Goessling et al.

    Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration

    Cell

    (2009)
  • H. Okada et al.

    Pathways of apoptotic and non-apoptotic death in tumour cells

    Nat Rev Cancer

    (2004)
  • A. Bergmann et al.

    Apoptosis, stem cells, and tissue regeneration

    Sci Signal

    (2010)
  • E.H. Baehrecke

    How death shapes life during development

    Nat Rev Mol Cell Biol

    (2002)
  • J.F. Kerr et al.

    Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics

    Br J Cancer

    (1972)
  • M. Lamkanfi et al.

    Alice in caspase land. A phylogenetic analysis of caspases from worm to man

    Cell Death Differ

    (2002)
  • X. Saelens et al.

    Toxic proteins released from mitochondria in cell death

    Oncogene

    (2004)
  • J.M. Adams et al.

    The Bcl-2 apoptotic switch in cancer development and therapy

    Oncogene

    (2007)
  • L. Galluzzi

    Cell death modalities: Classification and pathophysiological implications

    Cell Death Differ

    (2007)
  • A. Eisenberg-Lerner et al.

    Life and death partners: Apoptosis, autophagy and the cross-talk between them

    Cell Death Differ

    (2009)
  • A. Degterev et al.

    Expansion and evolution of cell death programmes

    Nat Rev Mol Cell Biol

    (2008)
  • P. Nicotera et al.

    Regulation of the apoptosis-necrosis switch

    Oncogene

    (2004)
  • Y.T. Wu et al.

    Autophagy plays a protective role during zVAD-induced necrotic cell death

    Autophagy

    (2008)
  • L. Yu et al.

    Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8

    Science

    (2004)
  • S.Y. Chen et al.

    zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation

    Autophagy

    (2011)
  • Cited by (47)

    • The role of dendritic cells in radiation-induced immune responses

      2023, International Review of Cell and Molecular Biology
    • Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence

      2019, Acta Biomaterialia
      Citation 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].

    • Effects of cell death-induced proliferation on a cell competition system

      2019, Mathematical Biosciences
      Citation 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].

    • Stochastic cellular automata model of tumorous neurosphere growth: Roles of developmental maturity and cell death

      2019, Journal of Theoretical Biology
      Citation 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 Advances
      Citation 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.

    View all citing articles on Scopus

    The authors declare no conflict of interest.

    View full text