Friday, July 6, 2012

STOP and GO and Cancer Cell Proliferation

In a recent paper by Solimini et al the authors discuss the concepts of STOP and GO genes and carcinogenesis[1]. The paper reports on some extensive experimental results focusing on the issue of proliferation and the loss of certain sets of gene sites, the STP and GO sites.

The authors begin by discussing the current concepts of changes in oncogenes and tumor suppressor genes, some of the key pathway elements that we examine in analyzing intracellular pathway dynamics. They state:

Cancer progression is directed by alterations in oncogenes and tumor suppressor genes (TSGs) that provide a competitive advantage to increase proliferation, survival, and metastasis. The cancer genome is riddled with amplifications, deletions, rearrangements, point mutations, loss of heterozygosity (LOH), and epigenetic changes that collectively result in tumorigenesis.

How these changes contribute to the disease is a central question in cancer biology. In his two-hit hypothesis,Knudson proposed that two mutations in the same gene are required for tumorigenesis, indicating a recessive disease. In addition, there are now several examples of haploinsufficient TSGs .

Current models do not explain the recent observation that hemizygous recurrent deletions are found in most tumors. Whether multiple genes within such regions contribute to the tumorigenic phenotype remains to be elucidated…

The last sentence regarding the inability to explain the presence of hemizygous deletions under the current model is the main driver for this effort. Thus they argue and demonstrate experimentally that:

Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions.

We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively.

STOP genes include many known tumor suppressors, whereas GO genes are enriched for essential genes.

Analysis of their chromosomal distribution revealed that recurring deletions preferentially over-represent STOP genes and under-represent GO genes.

We propose a hypothesis called the cancer gene island model, whereby gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted to maximize proliferative fitness through cumulative haploinsufficiencies.

Because hundreds to thousands of genes are hemizygously deleted per tumor, this mechanism may help to drive tumorigenesis across many cancer types.

This is an intriguing hypothesis. It adds more pieces to an already complex puzzle. The Cancer Gene Island, CGI, hypothesis seems to indicate the complex changes in multiple gene sites. In particular there was a deletion of the STOP genes in preference to the GO genes. Unfortunately there did not seem to be a mechanism for these deletions, however the experimental evidence does indicate the phenomenon.

In their experimental analysis they have observed certain in vitro results which compel their hypothesis. They state:

This in silico analysis suggests that the loss of a single copy of GO genes has a negative impact on cellular fitness. To independently test this hypothesis, we turned to the other arm of our screen that identified candidate GO genes whose depletion limits proliferation and survival. Because both normal and cancer cells are dependent on these essential GO genes, we analyzed data from proliferation screens on HMECs, one normal prostate epithelial cell line, and seven breast or prostate cancer cell lines

They provide an interesting pathway model as shown below (as mofified, and also not that they have short hairpin RNAs (shRNAs)).

They conclude as follows:

The enrichment for genes localized to deletions suggests that we have identified dozens of new TSGs in recurrent deletions. We have also likely identified more TSGs outside of these regions because the STOP gene set is (i) enriched for known TSGs, many of which are not found in recurrent deletions, and (ii) enriched for genes that undergo somatic loss-of-function mutation.

Finally, this work suggests that cells possess a substantial number of genes that restrain proliferation in vitro, which could be inactivated to promote clonal expansion during tumorigenesis in addition to the traditional driver genes currently known. Given the prevalence of multiple, large, recurring hemizygous deletions encompassing skewed distributions of growth control genes in tumors, we propose that the elimination of cancer gene islands that optimize fitness through cumulative haplo-insufficiencies may play an important role in driving tumorigenesis, with implications for the way in which we think about cancer evolution.

As with many such works this raises as many questions as it seems to answer. However the control or lack thereof of proliferation and the cell cycle is a critical issue in carcinogenesis.

[1] Solimini, N., et al, Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential, Science, 6 JULY 2012 VOL 337, p 104.