The epithelial ovarian cancer (EOC) disease is associated with peritoneal cavity in about 70 percent of EOC cases. The ovarian cancer cells usually are found distributed on the peritoneal surfaces of white adipose tissue and connective tissues. The EOC cells are mostly inclined to spread into peritoneal areas while they are morphologically similar to the cells derived from Mullerian ducts. Homeobox genes belong to a gene superfamily which is involved in managing the cell differentiation and specific strategy in embryonic development. Among the Homeobox gene families, the biggest one is the mammalian HOX family. This gene family comprises of 39 genes that are arranged in four clusters. The Mullerian system patterns are governed by the gene cluster HOXA. It was studied in a research that HOXA or Mullerian HOX gene expression is seen in many of the EOC subtypes. This Mullerian HOX gene program was responsible for the differentiation patterns similar to the Mullerian cells occurring in the EOC subtype. The researchers say that the evidence of relation between functioning of Mullerian HOX genes and the clinical significance of EOC is not observed till now.
The functioning and expansion of the epithelial cells and stromal cells are controlled by the exchange of information between these cells. The relationship between the tumor cells and stroma has shown impact on the growth of tumor. The important element of tumor stroma is cancer associated fibroblast which is known to have any destructive impact on the disease. The developmental programs running in the cells of the tumor are managed by cancer associated fibroblasts. In the present study, the authors have explored the role of HOX genes in the growth of EOC, disease outcome and tumor stroma. The other outcomes of the study are:
1. In the EOC patients as well as in the mouse xenograft models of EOC, the survival state was poor and it was associated with the HOXA9 gene expression.
2. The EOC growth was enhanced by HOXA9 gene expression by initiating the mesenchymal stem cells that were taken from adipose tissue, normal peritoneal fibroblasts and bone marrow tissue. By the stimulation of these cells by HOXA9 gene expression, the molecular and functional characteristics of cancer associated fibroblasts (CAFs) are attained by these cells through the initiation of TGF beta-2, which is discharged by the tumor.
3. The results of this study make us understand that the expression of the HOXA9 gene in EOC cells converts the stroma cells to become congenial for the tumor growth. The influence of the HOXA9 gene expression indicates primarily the importance of Mullerian patterning gene in the EOC performance.
The clinical significance of the Mullerian HOX genes were evaluated in this study which revealed that higher expression of HOXA9 gene led to higher mortality rate than the lower expression of the gene. The growth of EOC cells was observed InVivo and not InVitro. The EOC cells do not develop CAF like features with the HOXA9 expression while HOXA9 gene expression in EOC cells has resulted in CAF characteristics developed in omental fibroblasts as well as in mesenchymal stem cells which are derived from bone marrow and adipose tissue. This study also says that the impact of HOXA9 expression on fibroblasts is mediated by the stimulation of TGF-beta2 expression in EOC cells.
The stroma is made energetic by the HOXA9 expression in the EOC cells to support and enhance the tumor growth. The drug targets developed for HOXA9 transcript would be a big challenge. The drug that has inhibitory effect on the TGF-beta2 would be a favorable treatment strategy.
Song Yi Ko, Nicolas Barengo, Andras Ladanyi, Ju-Seog Lee, Frank Marini, Ernst Lengyel and Honami Naora. HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts. J Clin. Invest. (2012, Sep. 4th), doi:10.1172/JCI62229.