Our analysis reiterates that development of primary and recurrent ovarian disease involves quite different mechanisms, thousands of genes are differentially expressed. At the gene level, recurrent tumors appear to repress a cancer stemness signature related to p53 p21 regulation. In parallel, recurrent tumors recruit a population of miRNAs with close links to the development of highly malignant, poorly differen tiated tumors from nullipotent hEC cells. Different genetic profiles are employed by primary and recurrent ovarian tumors. In this study we demon strate that malignant stem cell differentiation genes are expressed in either primary tumors or both primary and recurrent tumors but essentially never in recurrent tumors specifically. Some CSC mechanisms are similarly employed in primary and recurrent tumorigenesis.

In addition, an obvious implication of our study is that CSCs that survive chemotherapy to repopulate recurrent disease can do so using different mechanisms than those employed in primary disease. Functional relationship analysis indicated that these stemness hop over to this site signature genes have a particular relevance to cellular proliferation and apoptosis. Several of the genes highlighted are known p53 p21 signaling regulators. Mechanistically this relates to regulation of p53 p21 processes, where p53 regulation is enhanced and p21 regulation no longer required in recurrent tumors. This is supported by increased expression of p21 repressing miRNAs in recurrent tumors and strong predicted targeting of p53 signaling genes by tumor specific miRNAs.

Altered p53 p21 regulation is the primary mechanism through which cancers avoid apoptosis and stimulate cellular prolifera tion. Predictably, we did not find loss of p53 or p21 in recurrent disease. It appears that {read this article|Micafungin Sodium datasheet p53 p21 regulation is required at both stages of ovarian malignancy. In Figure 6 we present a schematic to illustrate the p53 p21 regulators highlighted in out study. We propose that these genes and miRNAs regu late p53 p21 signaling, at least partially, in primary and recurrent disease. Indeed, this is likely to be a component of a larger mechanism. This p53 p21 regu lating component appears to play a role in primary tumors that is not used during recurrence. We refer to this as a p53 p21 regulating mechanism within the can cer stemness signature.

As a key tumorigenesis component, differential regulation of stemness linked p53 p21 mechanisms in primary and recurrent disease is an important outcome of this study and will be the subject of ongoing analysis. It is well established that EC and ES cells are highly similar in the undifferentiated and well differentiated states. This illustrates the significant challenges to the concept of targeting CSCs in a manner that does not harm the non malignant stem cell pool.