ABSTRACT
Tumor cells often differ genetically from normal cells and from one another. Competitive interactions can occur between genetically-distinct cells, and recent studies highlight multiple examples where cell competition initiates using distinct pathways.
Tumor cells generally differ genetically from normal cells, and further genetic differences often arise within tumors themselves. This raises the questions of how tumor development and evolution is affected by competitive processes between genotypes, and how tumor growth and properties could be affected, for better or for worse, by manipulating such processes. In recent years, there has been increasing study of competition that can occur between different genotypes that occur in non-tumor settings, and which may provide insights into tumor evolution. Here, we review recent studies that begin to identify the initial steps of competitive processes.
Morata and Ripoll described cell competition in Drosophila melanogaster wing development while studying growth properties of ribosomal protein (Rp) mutant cells. There was a loss of cells heterozygous for ribosomal protein mutants (Rp±) from mosaic wing primordia that also contained wild type cells. These ribosomal protein mutant cells were viable if wild type cells were not present. It is now known that this cell competition reflects apoptosis (programmed cell death) of ribosomal protein heterozygous cells when growing next to wild type cells. Cell competition has also been described between other differing genotypes. At least 17 distinct examples are now listed by recent reviews. These include competition between cells having different expression levels of proto-oncogene myc or between cells mutated for neoplastic tumor suppressors such as scribbled (scrib), discs large (dlg) or, lethal giant larvae (lgl), three proteins that are involved in apical-basal polarity of epithelial cells. Some of these cell competitions are also observed in mammalian cells and embryos. Cell competition might be a way for tissues to maintain homeostasis or might act as a quality control mechanism for elimination of suboptimal cells. For example, pre-neoplastic scrib, dlg or lgl cells tend to get outcompeted by neighboring normal cellsCitation1,Citation2. On the other hand, cell competition contributes to the expansion of tumor cells in the otherwise normal fly intestineCitation3.
Do these examples of cell competition between various genotypes of cells reflect common mechanisms? Recent studies that link initiation of cell competition to components of innate immunity, to mechanical stress, Slit-Robo signaling, changes in cell polarity, increased cell intercalation due to growth difference, or to regulatory signaling by ribosomes suggest there may be multiple pathways of cell competition ().
Table 1. Multiple pathways required for competition between genetically-distinct cells. Abbreviations: Rp – ribosomal protein; Scrib – Scribbled; Sas – Stranded-at-Second; PYP10D – Protein Tyrosine Phosphatase 10D; p53 – Tumor Protein p53.
In insects, innate immune pathways recognize bacterial and fungal pathogens. Although innate immunity proteins are involved in both competition between wild type and Rp+/- cells and between wild type and Myc-overexpressing cells, the components differ in each case. The secreted protein Spatzle activates nuclear-factor kappa-light-chain-enhancer of activated B cells (NF-kB) mediated apoptosis in both. Whereas during Rp+/- cell competition, Toll-Related-Receptor proteins 3 and 9 (TRR3 and TRR9) activate competitive apoptosis through the NF-kB family members Dorsal and Dorsal-related immunity factor and their inhibitor Cactus, in Myc induced competition, TRR 2,3,8, and 9 are required non-redundantly to activate competitive apoptosis by downstream effectors Dredd, Sterile alpha and TIR-motif containg protein 1 (Ect4) and the NF-kB family member RelishCitation4. It is not yet known whether innate immunity ligands and receptors directly recognize genetically different cells, or contribute to cell competition in another way.
Distinct signaling pathways have been implicated in competition of pre-neoplastic cells mutated for lgl, dlg, or scrib. This tumor-suppressive competition is partially independent of caspase-dependent apoptosis, unlike Myc or Rp+/- induced competitions, which are caspase dependentCitation1,Citation4,Citation5. Instead pre-neoplastic cells are also extruded in both apical and basal direction in response to their healthy neighborsCitation1. Extrusion of scrib mutant cells involves Slit-Robo2 signaling through Enabled/Vasp (Ena), an actin nucleator that downregulates E-cadherin and also affects the actomyosin networkCitation1. Slit-Robo2 signaling is induced cell autonomously by elevated JNK signaling in scrib mutant cellsCitation1, but the extrusion of scrib mutant cells needs the presence of wild type neighbors. The wild type cells use Stranded at second (Sas) to activate the receptor Protein Tyrosine Phosphatase 10D (PTP10D) in scrib mutant cells specifically at the boundaryCitation2. PTP10D signaling suppresses Epidermal Growth Factor Receptor (EGFR) signaling which otherwise would get hyper-activated in scrib mutant cells to inhibit Jun N-terminal Kinase (Jnk) to promote proliferation and tumorigenesis. This suppression can only happen where there are wild type cells available to activate PTP10D. The Sas and PTP10D genes that are required in scrib induced competition are not required for Rp+/- or Myc induced competitionCitation2.
Recent reports show related cell competition pathways in mammals. During early mouse development, epiblast cells that have less Myc get outcompeted by neighboring cells with higher MycCitation6. Mammalian Madin-Darby Canine Kidney (MDCK) cells knocked-down for scrib get outcompeted by neighbors in tissue cultureCitation7. The mechanics of differential growth in this mixed epithelium elevate Tumor Protien p53 (TP53, better known s p53) levels until the scrib knockdown cells become hyper-sensitive to compactionCitation7. Interestingly, p53 loss can also make otherwise normal cells more competitive in the mouse embryoCitation8. This implies that mammalian cells are under selective pressure that can activate cell competition mechanisms, but the implications of this in tumorigenesis or other disease needs more investigation. In contrast to the prominent roles of p53 during mammalian cell competition, its role in Drosophila does not seem to be the same. Rp+/- cells still can be eliminated without p53 function, and when wild type cells are eliminated by competition with cells expressing more Myc, surprisingly it is the cells with more Myc that require p53Citation5,Citation9.
Drosophila genetics remains a valuable tool for discovering mechanisms of cell competition, and a new signal has now been found in the cell competition between Rp+/- cells and wild type cells. Whenever a Rp gene is mutated, one particular ribosomal protein is important for initiating competitionCitation10. This special ribosomal protein, RpS12, is an essential protein like other ribosomal proteins but it has an additional role in determining competitiveness. This is revealed when Rp+/- cells that have more RpS12 get eliminated by Rp+/- neighbors that have less RpS12 (where the Rp+/- genotype affects any other ribosomal protein gene). Therefore, it seems that this cell competition depends on different relative levels of RpS12 activityCitation10. The molecular mechanism of RpS12 signaling is not yet known. RpS12 may define specialized ribosomes with a special role in cell competition. Another possibility is that RpS12 has an extra-ribosomal competition function. Future studies are needed to resolve this and investigate the possible role of RpS12 during mammalian cell competition.
Cell competition has been suggested to play various roles during development, regeneration and, tumorigenesis. These recent reports make it clear that cells can follow different pathways to initiate cell competition. The innate immune components involved in Rp+/- and Myc induced competition are partially distinctCitation4. RpS12 is crucial in competitive elimination of Rp+/- cells but is not required for Myc induced competitionCitation10, meanwhile the Sas/PTP10D and Slit/Robo signals that eliminate preneoplastic cells are not important for eliminating Rp+/- cellsCitation1,Citation2. p53 is important in most of the mammalian cell competition examples studied but in Drosophila its role is not the sameCitation5,Citation7–Citation9. If multiple pathways lead to distinct examples of cell competition this will need to be taken into account when considering the pathological and therapeutic possibilities of cell competition.
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References
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