Néstor J. Oviedo and Wendy S. Beane- Regeneration: The Origin of Cancer or a Possible Cure?

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  NIH Public Access Author Manuscript Semin Cell Dev Biol. Author manuscript; available in PMC 2010 July 1. Published in final edited form as: Semin Cell Dev Biol. 2009 July ; 20(5): 557–564. doi:10.1016/j.semcdb.2009.04.005. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Regeneration: The Origin of Cancer or a Possible Cure? Néstor J. Oviedo* and Wendy S. Beane Center for Regenerative and Developmental Biology &, Department of Biology, Tufts University, 200 Boston Av
  Regeneration: The Origin of Cancer or a Possible Cure? Néstor J. Oviedo *and Wendy S. Beane Center for Regenerative and Developmental Biology &, Department of Biology, Tufts University,200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, U.S.A Abstract A better understanding of the forces controlling cell growth will be essential for developing effectivetherapies in regenerative medicine and cancer. Historically, the literature has linked cancer and tissueregeneration—proposing regeneration as both the source of cancer and a method to inhibittumsrcenesis. This review discusses two powerful regeneration models, the vertebrate urodeleamphibians and invertebrate planarians, in light of cancer regulation. Urodele limb and eye lensregeneration is described, as well as the planarian’s emergence as a molecular and genetic modelsystem in which recent insights begin to molecularly dissect cancer and regeneration in adult tissues. Keywords regeneration; cancer; stem cells; wound healing; amphibians; planariansThe individuation field, then, is the agent which controls the growth of the differentparts in a harmonious way so that a normal individual is formed. In later life, theindividuation field splits up into smaller separate fields, such as leg fields, head fields,etc. These are the agents from which cancerous growth has escaped.(Conrad H. Waddington, 1935). 1. Introduction In his 1935 treatise, Waddington considers the mechanistic connection between uncontrolledcancerous growth and controlled embryonic development, postulating the existence of “individuation fields” that regulate tissue growth both during embryonic development and inadult tissues [1]. Interestingly, Waddington’s description of “individuation fields” is evocativeof regenerative fields, and he himself links a field’s strength to the organism’s regenerativeability. Modern interpretation of Waddington’s theory, which remains untested and largelyoverlooked in the current literature [2], implicates regeneration mechanisms as possible cancerregulators and underscores the need to investigate links between regeneration and cancer.The term regeneration implies a well-coordinated restoration of cells, tissues, and organs thathave been physically or functionally lost. This reparative process must accomplish therecognition and recapitulation of missing structures, while simultaneously achieving functional *Author for correspondence: Néstor J. Oviedo, Center for Regenerative and Developmental Biology &, Department of Biology, TuftsUniversity, 200 Boston Avenue, suite 4600, Medford, MA 02155-4243, U.S.A. E-mail: E-mail: nestor.oviedo@tufts.edu, Phone:617-627-4070, Fax: 617-627-6121. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resultingproof before it is published in its final citable form. Please note that during the production process errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Semin Cell Dev Biol . Author manuscript; available in PMC 2010 July 1. Published in final edited form as: Semin Cell Dev Biol . 2009 July ; 20(5): 557–564. doi:10.1016/j.semcdb.2009.04.005. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    integration between recently formed and pre-existing tissues, in order to direct physiologicaland structural alterations. Furthermore, regeneration involving cellular proliferation(epimorphosis [3]) requires instructive signals with the capacity to efficiently regulate cellcycle, resulting in a finite number of cells that undergo division and complete repairs [4–7].Participating cells must be precisely guided to needed areas, and once regeneration is completespecific cues are required to report regenerative success and signal termination. Otherwise, theinitial response would continue indefinitely, causing undesirable consequences for bodyhomeostasis. Diverse regenerative phenomena appear to utilize similar mechanisticprocedures, including: cellular replacement (e.g., physiological cell turnover), local tissuerepair (e.g., epithelial wound repair), and regeneration of large sections (e.g., appendages andhead) [4,7–12].Independent of magnitude, a regenerative event always seeks to maintain or reestablish bothform and function (morphostasis). However, the process is not infallible, as demonstrated bygrowing evidence associating regeneration with cancer-related cellular abnormalities [1,8,10,13–19]. Owing to space limitations, this review will be restricted to analyses of the relationshipof abnormal cell proliferation and cancer to injury-induced epimorphic regeneration in adultanimals. Readers interested in the relationships between cell turnover and regeneration arereferred to a recent review [9]. Despite extensive accumulated data on epimorphic regeneration(both blastemal and non-blastemal [6]) consistently linking regeneration and cancer, we stilllack a mechanistic connection [1,8,10,13–18,20–23].Seemingly contradictory, regeneration might in fact both contribute to the source of abnormalgrowth and also provide a means to prevent and correct growth abnormalities. The initialphenomenological observations were summarized by Seilern-Aspang and Kratochwil, whosurveyed the classical data and proposed two nonexclusive hypotheses: (i) the formation of malignant tumors derives from an impaired or incomplete regenerative process (Fig. 1A), and(ii) the regeneration process may bring under control the autonomous growth of malignant cells(Fig. 1B) [16]. The first hypothesis is largely based on observations of local tissue repair inmammals, where epithelial surfaces exposed to chronic damage or hypoxic conditions andinflammation result in growth aberrations during the regenerative response [8,10,13,15,16,19,23,24]. It is important to note this is not universal to all cancers but is perhaps more likelyin those of epithelial srcin. Interestingly, alterations of this process are probably associatedwith loss of tissue formation, remodeling (morphogenesis), and termination signals, whereasthe capacity to sense damage and activate cell proliferation may not in fact be impaired. Thissuggests characterizing the signals associated with later regeneration events may be useful inidentifying candidates that halt abnormal cell proliferation (leading to cancer). The secondhypothesis conversely suggests that if induced cellular proliferation during regeneration isfollowed by morphogenetic processes, regeneration has the potential to prevent abnormalgrowth and more startling, to reverse malignancies and regain morphostasis—phenomenamostly observed in animals with immense regenerative potentials [1,14,16,17,21,25–27]. It isintriguing that biological responses associated with epimorphic regeneration lead to completelyopposite outcomes—in one instance destruction, while in another rebuilding and reestablishingform and function. It is the latter of these outcomes that is the major concern of this review.Cancers have been regarded as wounds that never heal, and the possible relationships betweencarcinogenesis, inflammation and local tissue repair (wound healing) have been extensivelyreviewed elsewhere [8,10,13,19,24]. This article will focus on two adult animal models, thevertebrate urodeles and the invertebrate planarians, that have been traditionally used to studythe relationships between large-scale regeneration and malignant transformation. In addition,we will briefly survey some of the approaches and data (mostly classical) concerning cancerand the different regeneration methods in urodele amphibians and planarians. Finally, recentmolecular approaches targeting evolutionarily conserved signaling pathways in planarians will Oviedo and BeanePage 2 Semin Cell Dev Biol . Author manuscript; available in PMC 2010 July 1. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    be discussed, highlighting the relevant consequences that may serve as an entry point forunraveling the molecular bases linking cancer and regeneration in adult organisms. 2. Urodeles and Planarians as Models for Studying Regeneration and Cancer Although many different model animals, developmental stages, and in vitro systems have beenutilized to study cancer and regeneration independently, two organisms, the urodeleamphibians (including newts and axolotl) and planarians (flatworms), have risen to theforefront for simultaneously exploring malignant transformation and adult regeneration [1,14,17,25,26,28,29]. The interest in these two particular groups comes from their extraordinaryregenerative capacities, which have been explored for over 200 years [4–6,11,22,30–35], aswell as their distinct capacities for chemically-induced carcinogenesis [14,17,26,29,36–38].Remarkably, even though urodeles and planarians both undergo epimorphic regeneration, thecellular mechanisms they use to repair missing parts and their sensitivities to carcinogens differ.For example, in adult newts injury causes differentiated post-mitotic cells to re-enter the cellcycle and dedifferentiate, while in planarians the main regeneration strategy involvesproliferation of resident adult somatic stem cells known as neoblasts [5,11,31,33–35,39].Fascinatingly, while regenerative tissues in urodele amphibians display a low frequency of tumor development upon carcinogenic exposure [14,16,17,40], treatment of whole planarianswith similar chemicals can lead to abnormal proliferation and tumor formation [16,20,29,36–38,41,42]. Given the astonishing regenerative capacities of both planarians and urodeles, theirdifferential responses to carcinogens offer a unique opportunity to examine Waddington’stheory that “individuation fields” controlling growth are the source from which “cancerousgrowth has escaped” [1].These two models of epimorphic regeneration evoke a provocative scenario where well-orchestrated molecular events shape growth and morphogenesis in adult tissues by preventingrandom growth aberrations during the reversal of differentiated states (urodele) and abnormalstem cell proliferation during de novo tissue formation (planarians). Most of our currentknowledge regarding cancer and regeneration in both amphibians and planarians comes fromclassical studies using chemically-induced carcinogenesis. In these studies, treatment withsubstances known to produce permanent DNA alterations were used, followed by histologicaland behavioral analyses to evaluate effects. These data consist mostly of phenomenologicalobservations lacking the resolution achievable with modern molecular and genetic techniques.The following sections provide an overview of our current understandings about the specificregenerative properties and cancer associations for each model system. 3. Urodele Amphibians and Cancer Adult newts and axolotls possess amazing regenerative potential. The newt, for example, canregenerate tail, limbs, brain, spinal cord, retina, and lens [4,5,11,22,30,39]. Although thesevertebrates regenerate multiple tissue types, the analyses here are restricted to regeneration of adult newt limbs and lens because these tissues have been more extensively studied and relatedto cancer. The processes of lens and limb regeneration demonstrate an incredible degree of plasticity, where both differentiated pigment epithelial (PE) cells from the dorsal iris as wellas limb mesenchyme reverse their differentiated state by re-entering the cell cycle. In bothcases, this cellular dedifferentiation implies a loss of tissue-specific characteristics (bringingcells close to a undifferentiated state) followed by re-differentiation into cells of the same typeor even a different lineage [30]. More importantly, this process can be repeated over and overwithout variation—a feature apparently missing in mammalian models where chronic localwound repair can lead to certain epithelial cancers [8,13,15]. Nonetheless, while both newttissues undergo epimorphic regeneration, the processes are sufficiently distinct that sub- Oviedo and BeanePage 3 Semin Cell Dev Biol . Author manuscript; available in PMC 2010 July 1. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    classifications of regeneration have been proposed [6]. In lens regeneration cellulardedifferentiation, transdifferentiation (epithelial cells to lens), and proliferation are observed[11,14,43], while in limb regeneration dedifferentiated cells participate in the formation of theregeneration blastema (basically a mesenchymal growth zone where missing parts are rebuilt)[4,5,11,14,22,39,44,45]. Thus, adult tissue regeneration in urodeles provides a useful settingwhere transdifferentiation and blastema formation can be analyzed to elucidate how cellsfollowing injury are able to reverse their differentiated state and proliferate and yet escape thepitfalls of malignant transformation. 3.1. Lens Regeneration and Cancer Shortly after lens removal, dedifferentiated PE cells of the dorsal (but not ventral) iris lose theirpigmentation and begin to elongate, differentiating into primary lens fiber cells; cellproliferation and crystallin synthesis follows, rebuilding the missing lens in about 25 days[11,14,43]. Lens regeneration in adult newts provides an exquisite model for studying cellularplasticity, because within the same organ structurally similar components display fundamentaldifferences in regeneration potentials—while the dorsal iris is a source for regeneration, theseemingly similar ventral iris is not. Only a few studies have addressed the possible applicationof urodele lens regeneration to cancer research. In most of these studies, potent carcinogeniccompounds such as nickel subsulfide, known to induce chromosomal abnormalities and DNAstrand breaks (and in other vertebrates, abnormal outgrowth and cancers), were used as a meansto evaluate cancer and regeneration simultaneously [17,26,46–50].In the majority of these studies carcinogenic compounds were introduced locally within theeye, and the consequences of such treatments during lens regeneration can be summarized asfollows (Fig. 2A): (i) regeneration proceeded normally compared to untreated animals, (ii)supernumerary lenses arose from the ventral iris without additional abnormalities, or (iii) insome cases there was a delay of several months (or complete inhibition) of regenerationaccompanied by production of melanoma-like ocular tumors srcinating exclusively from theventral iris. These results strongly support the belief that regenerative tissue is significantlyunlikely to form cancerous abnormalities. This is particularly well illustrated in the newt lens,since the dorsal iris (capable of regenerating lens) does not act as a source of abnormal cells,while its non-regenerating counterpart (the ventral iris) responds to carcinogenic insults byforming abnormal cells that give rise to tumors.Under these conditions, the dorsal iris is basically resistant to tumor formation without anyeffect on its regenerative response. Even when exposed to higher concentrations of carcinogenic compounds, the dorsal iris simply stops regenerating (still without formingtumors). Conversely, in the ventral iris these chemicals have the capacity to unlock a highlyuncoordinated regenerative potential that can produce supernumerary lenses or even malignanttransformations leading to aggressive tumors. Therefore, the differences between the dorsaland ventral iris are not restricted to their regenerative potentials, but also include their abilitiesto respond to cancer-inducing cues, suggesting a link between regeneration and canceravoidance. Interestingly, this can be analyzed simultaneously in vivo , as has been previouslyshown [26]. Thus, the lens regeneration paradigm provides an entry point for dissectingmolecular differences between regenerative and non-regenerative tissues [51], as well as theopportunity to investigate Waddington’s “individuation fields” and their differentialcapabilities in regenerative versus non-regenerating tissues [1]. 3.2. Limb Regeneration and Cancer There is an impressive amount of literature associated with limb regeneration in urodeles.While this is arguably the most studied subject in vertebrate appendage regeneration, themolecular mechanisms remain elusive. Recently, several molecular and genomic tools (e.g. Oviedo and BeanePage 4 Semin Cell Dev Biol . Author manuscript; available in PMC 2010 July 1. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  
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