Epithelial Polarity and Proliferation Control: Links from the Drosophila Neoplastic Tumor Suppressors

Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors David Bilder1 Department of Molecular and Cell Biology, University of California, Berkeley, Berkelely, California 94720-3200, USA Mammalian epithelial tumors lose polarity as they Subsequent years saw the isolation of additional tu- progress toward malignancy, but whether polarity loss mor-causing mutations in Drosophila, and the similari- might causally contribute to cancer has remained un- ties between the Drosophila tumors and human tumors, clear. In Drosophila, mutations in the “neoplastic tumor outlined in Gateff’s 1978 review in Science (Gateff 1978), suppressor genes” (nTSGs) scribble, discs-large, and le- initially occasioned significant interest. However, as hu- thal giant larvae disrupt polarity of epithelia and neuro- man and fly TSGs were cloned, the lack of overlap in blasts, and simultaneously induce extensive overprolif- protein sequence, cellular localization, and proposed eration of these cells, which exhibit malignant-like char- function led to decreasing attention from cancer biolo- acteristics. Herein I review what is known about the role gists. Moreover, as it became appreciated that human of the fly nTSGs in controlling cell polarity and cell pro- cancer results from multiple genetic lesions, the rel- liferation. Incorporating data from mammalian studies, I evance of fly models in which loss of a single gene could consider how polarity and proliferation can be coupled, lead to dramatic overproliferation aroused skepticism. and how disruption of polarity could promote cancer. From an auspicious beginning, Drosophila became rather overlooked as a model system for cancer studies. Recent years have seen a remarkable turnaround. The In 1967, Elizabeth Gateff and Howard Schneiderman potential of fly research to address difficult questions in published a short note in the American Zoologist de- the etiology of cancer (as well as distinctively human scribing a Drosophila mutation that caused affected cells pathologies such as Alzheimer’s and Parkinson’s dis- to “grow rapidly and invasively and kill their hosts” eases) is newly appreciated (Bernards and Hariharan (Gateff and Schneiderman 1967). The mutant cells “[be- 2001). Drosophila has come into its own in particular as haved] like a malignant tumor.” This mutation, lethal a system in which to identify new TSGs, and the rel- giant larvae (lgl), acted in a recessive fashion, and was evance of fly TSGs to human cancer has become increas- thus distinct from the transforming oncogenes identified ingly clear. The past few years have seen reports that shortly thereafter. The potential existence of “recessive TSGs first identified in the fly are mutated in human oncogenes” had long been appreciated, dating back to cancers and can cause tumor susceptibility in mice (e.g., Boveri (Boveri 1929). However, Gateff and Schneider- St John et al. 1999; Spruck et al. 2002; Fuja et al. 2004; man’s announcement was the first example in vivo of a Rajagopalan et al. 2004). Analyses of fly TSGs have also gene in which loss of function resulted in tumor forma- produced substantial contributions toward understand- tion (Gateff and Schneiderman 1967). Thus, prior to ing the basic cell biology of tumorigenesis, in particular Knudson’s epidemiological evidence that the retinoblas- links between cell growth, cell proliferation, and apopto- toma (Rb) locus in human populations acted recessively sis. (Knudson 1971), and contemporary with Harris’s so- The unbiased genetic screens possible in Drosophila matic cell hybrid experiments that gave rise to the term have often provided entry points into studies of phenom- “tumor suppressor” (Harris et al. 1969), Drosophila pro- ena that have been recalcitrant to other approaches. In vided the first example of a tumor-suppressor gene mammalian tumor biology, one such phenomenon con- (TSG). cerns the transition of tumor cells from benign overproliferation to a fully transformed, malignant phenotype. In carcinomas (malignant tumors of epithelial origin), [Keywords: Polarity; proliferation; Drosophila; tumor suppressor; epithelia; cancer] one of the primary diagnostic features of transformation 1Correspondence. is a pronounced disorganization of cell architecture. The E-MAIL [email protected]; FAX (510) 642-8614. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ relationship between loss of epithelial organization and gad.1211604. progression toward malignancy in mammalian tumors GENES & DEVELOPMENT 18:1909–1925 © 2004 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/04; www.genesdev.org 1909 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Bilder has long been known, but whether this is merely cor- inducing clones via mitotic recombination makes them relative or whether loss of architecture might have some amenable to mosaic analysis as well as measures of dou- causative contribution to tumorigenesis remains a com- bling times. Most screens for proliferation mutants have pelling and critically important question. been performed using imaginal discs, although muta- Remarkably, research on the original fly TSG—lgl—is tions that affect the proliferation of nonepithelial cells, now providing insight into this issue. lgl, along with a such as the neuroblasts, germ cells, and hemocytes, have second gene, discs-large (dlg), controls not only cell pro- also been identified (Watson et al. 1994). liferation but also epithelial organization. Recently, the It is important to distinguish between the several identification of a third gene in this class, called scribble groups of Drosophila genes that have been referred to as (scrib), and the finding that the three genes act together TSGs. For instance, Drosophila contains homologs of in a single pathway, has raised interest in the possibility most known human tumor suppressors, including p53, that studies of lgl, dlg, and scrib will reveal a molecular Rb, NF1, and APC (Sutcliffe et al. 2003). Mutations in mechanism by which growth control and cellular archi- these genes have been generated through reverse genet- tecture are linked. This review provides a context to con- ics, and analyses of their phenotypes in the fly have sider what studies of these fly TSGs tell us about links helped clarify their roles in vertebrate cancer. However, between tumor suppression and cell architecture. I first many of these mutations themselves do not cause over- discuss the functions of lgl, dlg, and scrib, and then con- proliferation in the fly, and by this criterion are not in fly sider what aspects of their mutant phenotypes may pro- TSGs. vide informative parallels to human cancer. Finally, I The “true” fly TSGs can be considered those that, speculate on the mechanisms by which polarity and pro- when mutated, cause cellular overproliferation leading liferation could be coupled in epithelial tissues, and to tissue overgrowth (tumors). Fly tumors have tradition- highlight mammalian data that are consistent with this ally been subdivided into two groups, hyperplastic and concept. neoplastic. In “hyperplastic” tumors, imaginal discs con- tain increased cell numbers, but, despite often extensive overproliferation, the cells are normally shaped and re- Drosophila tumor suppressors: one term, many types main arranged in an epithelial monolayer, ultimately dif- Before discussing fly TSGs, it is important to consider ferentiating into adult tissues. Hyperplastic tumors can what is meant by a fly tumor. A minimal definition of a be caused by inactivating mutations in genes that regu- tumor encompasses a mass of overproliferating tissue late cell (as opposed to tissue) growth (e.g., PTEN, Tsc1/ whose growth is irreversibly uncoordinated from that of 2, salvador, warts, hippo; for review, see Pan et al. 2004), normal cells. Several types of abnormal growths, induced in genes that coordinate proliferation and cell death by genetic changes in the fly, meet these criteria. Al- (again salvador, warts, hippo; for review, see Rothenberg though the similarity is necessarily inexact, it is reason- and Jan 2003), or genes that function in a pathway ap- able to call these growths fly tumors. parently limiting total organ size (e.g., fat, ex; for review, The literature on insect or, indeed, invertebrate tu- see Johnston and Gallant 2002). In contrast, in “neoplas- mors in wild populations is quite thin (Harshbarger and tic” tumors, which are caused by mutations in lgl, dlg,or Taylor 1968). Drosophila tumors have been found seren- scrib, the overproliferating cells lose the ability to orga- dipitously as well as through genetic screens that seek to nize an epithelial monolayer. Neoplastic cells are identify mutations causing excess cell proliferation. The rounded rather than polygonal, and pile up atop one an- majority of these mutations act in a recessive rather than other as they overproliferate; they are incapable of ter- dominant manner. They therefore do not act as onco- minal differentiation. The use of the terms hyperplastic genes but instead as TSGs. There have been objections to and neoplastic to distinguish between Drosophila tu- the broadening and varied usage of the TSG designation mors that retain or lose epithelial organization has over the years, and in particular its application to non- caused some confusion among cancer

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