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Cell polarity and cancer essays in biochemistry

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Chalmers and Paul Whitley Cell wars: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract During cell cell polarity and cancer essays in biochemistry fitter cells take over the tissue at the expense of viable, but less fit, cells, which are eliminated by induction of apoptosis or senescence. This probably acts as a quality-control mechanism to eliminate suboptimal cells and safeguard organ function. Several experimental conditions have been shown to trigger cell competition, including differential levels in ribosomal activity or in signalling pathway activation between cells, although it is unclear how those differences are sensed and translated into fitness levels.

Many of the pathways implicated in cell competition have been previously linked with cancer, and this has led to the hypothesis that cell competition could play a role in tumour formation.

Cell competition could be co-opted by cancer cells to kill surrounding normal cells and boost their own tissue colonization. However, in some cases, cell competition could have a tumour suppressor role, as cells harbouring mutations in a subset of tumour suppressor genes are killed by wild-type cells. Originally described in developing epithelia, competitive interactions have also been observed in some stem cell niches, where they play a role in regulating stem cell selection, maintenance and tissue repopulation.

  1. For example, slow-growing Minute cells behave as losers next to normally growing wild-type cells; in turn, wild-type cells behave as losers next to cells that grow faster, e. Thus cell competition could also play a role in Wnt-induced cancers.
  2. How are loser cells instructed to die by neighbouring winner cells? Thus a better understanding of how polarity is established and maintained in epithelial cells will help us to understand the process of malignant transformation and may lead to improved therapies.
  3. This probably acts as a quality-control mechanism to eliminate suboptimal cells and safeguard organ function.
  4. The establishment and maintenance of apico—basal cell polarity is a pre-requisite for the formation of a functioning epithelial tissue many lines of evidence suggest that cell polarity perturbations favour cancer formation, even though the mechanistic basis for this link remains unclear studies in drosophila have uncovered complex interactions.

Thus competitive interactions could be relevant to the maintenance of tissue fitness and have a protective role against aging. Introduction Cell competition occurs when cells with different fitness levels confront one another.

It results in the elimination of the weaker population through apoptosis or senescence, whereas the stronger population survives and proliferates. Originally described in developing epithelia, competitive interactions have been linked with tissue homoeostasis, organ size control and stem cell maintenance.

Recent work also suggests that they may play a role in tissue regeneration and in cancer development. In the present chapter we will introduce the pathways implicated in initiating competition and report on our current understanding of the mechanisms involved in this process. Pathways of cell competition Cell competition was discovered in 1975, through characterization of the growth defects of Minute heterozygous mutations in Drosophila wing imaginal discs [ 1 ].

Minute M genes encode ribosomal subunits. Thus homozygous mutations are lethal due to a lack of functional ribosomes; however, heterozygous animals are viable and display just a developmental delay and minor morphological abnormalities. This suggested that competition could act as a surveillance system to actively remove mutant defective cells from the tissue.

In 2004, Oliver et al. Over 20 years after these first observations were made, Johnston et al. Cells with low levels of dMyc, because of a mutation in the corresponding gene, were lost in the presence of wild-type cells, but were viable when surrounded by the same cells.

Moreno and Basler [ 6 ] and de la Cova et al. In other words, the outcome of competition is context-dependent and cells become winners or losers depending on the fitness of their neighbours. This work confirmed the concept of supercompetitors: The discovery of supercompetitors established the initial link between cell competition and cancer.

The human homologue of dmyc is an established proto-oncogene, controlling the expression of many other genes involved in growth and proliferation and is frequently overexpressed in tumours [ 9 ]. Thus it was proposed that, similarly to what had been observed in Drosophila, cancer cells with high Myc levels could cause the elimination of surrounding normal cells, creating space in which to expand.

This view was further strengthened when mutations in tumour suppressors also gave rise to supercompetitors. The Hippo pathway modulates cell survival and proliferation and thus safeguards against neoplastic growth. Inactivation of cell polarity and cancer essays in biochemistry pathway through yorkie overexpression or mutations in fat, expanded or warts enables cells to eliminate surrounding wild-type tissue [ 1011 ]. Similarly, Vincent et al.

In this study, cells that cannot transduce the Wnt signal or cells that overactivate the pathway APC or Axin mutant were juxtaposed to wild-type cells. In both cases, those cells with relatively lower Wnt signalling levels were eliminated.

Wnt signalling is overactivated in a number of cancers and Axin and APC are frequently mutated tumour suppressor cell polarity and cancer essays in biochemistry [ 13 ]. Thus cell competition could also play a role in Wnt-induced cancers.

Tumour-suppressor-based mechanisms of cell competition have also been studied in vivo in a mammalian system. The transcription factor p53 is one of the best-known and most studied tumour suppressor genes [ 14 ].

Bondar and Medzhitov [ 15 ] characterized a form of cell competition induced by stress and mediated by p53. Doing repopulation assays in lethally irradiated bone marrow, they found that in the mouse haemopoietic stem cell, niche cell competition selects for the least damaged cells by comparing levels of p53 activity and selecting those cells with relatively lower p53 levels.

This work, carried out with mouse HSPCs haemopoietic stem and progenitor cellsshows that competition is not restricted to epithelial tissues.

In addition cell polarity and cancer essays in biochemistry this study, the occurrence of cell competition in stem cell niches has also been reported in the Drosophila ovary and testis [ 16 — 19 ]. Moreover, cell competition has been shown during liver repopulation assays in rats [ 20 ].

The above tumour suppressor mutations induce a supercompetitive behaviour; however, this is not always the case, loss-of-function of the tumour suppressor genes scrib scribble or lgl lethal giant larvae leads to their elimination by the surrounding wild-type cells, both in Drosophila mosaic discs and mammalian cells [ 21 — 24 ].

Thus not all tumour-promoting mutations lead to a competitive advantage, and in some cases precancerous cells can be eliminated by cell competition. How do mutations alter the competitive status of a cell and what cellular events take place during competition? We review the current knowledge in the following sections. Sensing cellular fitness By far the most mysterious aspect of the cell competition process is to understand how cells sense and compare fitness levels across tissues.

What are the signals and mechanisms that cells use to compare fitness and how are less fit cells identified and earmarked as losers? Several studies have highlighted a correlation between differential proliferation rates and cell competition. For example, slow-growing Minute cells behave as losers next to normally growing wild-type cells; in turn, wild-type cells behave as losers next to cells that grow faster, e. However, not all manipulations that increase growth rates appear to be sufficient to change the competitive status of a cell.

For example boosting cellular growth by overactivating the insulin pathway is not sufficient to induce a super-competitor status [ 7 ].

Cell wars: regulation of cell survival and proliferation by cell competition

Therefore it is possible that cells do not compare growth rates; rather they sense differences in a parameter, whose changes mirror differences in growth rates in some instances. Another clue in understanding how cells sense relative fitness levels comes from the many reports indicating cell polarity and cancer essays in biochemistry disparities in some signalling pathways often lead to cell competition.

Thus, although it is unclear how signalling levels are translated into fitness levels, it appears that several signalling pathways are able to modulate the levels of cell fitness that are compared during cell competition.

A recent breakthrough in the study of cell competition has come from the identification of a trio of proteins as important components of the fitness-sensing process. Performing transcriptional profiling of competing cells, Moreno and co-workers [ 28 ] showed that three differently spliced isoforms of the flower gene become differentially expressed in several contexts where competition is induced: Importantly, expression of either FlowerLose isoform is necessary and sufficient for the elimination of loser cells [ 28 ].

The mechanism of action of the Flower proteins and how they induce death in losers is entirely unknown at present. Flower has been described in another study as a calcium transporter [ 29 ]; however, it is unclear whether this function is required for its role in competition. Since they are transmembrane proteins, it is likely that Flower proteins are involved in extracellular recognition events between winners and losers.

However, it is worth noting that, since FlowerLose isoforms are not present at the onset of competition and become expressed only as competition is triggered, additional molecules must be responsible for the early sensing events that lead to the differential expression of the Flower isoforms.

The identification of membrane proteins as integral components of the fitness-sensing process indicates that some aspects of cell competition require cell—cell contact [ 28 ].

Moreover, additional studies have shown that competitive interactions are observed at a short range ranging from direct proximity [ 30 ] to a few cell diameters away [ 7 ]. However, independent experiments in cell culture show that cell competition can still happen if winner and loser cells share the same culture medium but are not allowed direct contact [ 31 ].

Therefore it is possible that multiple independent molecular pathways initiate competition and that some of those are mediated by soluble factors. The nature of these factors remains to be identified: Interestingly, in the context of competition induced by Wnt signalling, high-Wnt cells release Notum, a diffusible Wnt inhibitor that is required for the outcompetition of low-Wnt cells [ 12 ]. Notum does not take part in the fitness-sensing process, but contributes to competition by lowering the Wnt signalling levels and hence fitness of surrounding wild-type cells.

Elimination of loser cells As described in the Introduction, a key feature of cell competition is the non-autonomous induction of death in the weaker population. How are loser cells instructed to die by neighbouring winner cells?

With one exception, in which loser outcompetition happens via induction of senescence rather than death discussed belowloser cells are killed by apoptosis Figure 1. However, while this is a common denominator, several independent upstream pathways have been shown to trigger the apoptotic event during cell competition. Their involvement seems to be context-dependent and influenced by the specific type of cell competition studied and possibly by the tissue studied Figure 1 A.

  1. Cell polarity and cancer essays in biochemistry Work in the nabi lab focuses on cell biology and its relation to disease, in particular cancer the expression of cellular domains, ranging from cell polarity to organelle biogenesis to membrane microdomain organization, plays an important role in regulating cell function domain localization is critical to the regulation of receptor activation and.
  2. Abstract During cell competition fitter cells take over the tissue at the expense of viable, but less fit, cells, which are eliminated by induction of apoptosis or senescence.
  3. This work, carried out with mouse HSPCs haemopoietic stem and progenitor cells , shows that competition is not restricted to epithelial tissues.
  4. The establishment and maintenance of apico—basal cell polarity is a pre-requisite for the formation of a functioning epithelial tissue many lines of evidence suggest that cell polarity perturbations favour cancer formation, even though the mechanistic basis for this link remains unclear studies in drosophila have uncovered complex interactions.
  5. Cells with low levels of dMyc, because of a mutation in the corresponding gene, were lost in the presence of wild-type cells, but were viable when surrounded by the same cells. Minute M genes encode ribosomal subunits.