Wnt and Hedgehog Gene Pathway Expression in Serous Ovarian Cancer

Ovarian cancer is the leading cause of death from gynecological cancer in the United States, with estimated 13,850 deaths in 2010. Most patients are initially diagnosed with stage III or IV disease. Despite good responses to the initial treatment, which includes surgery followed by che-motherapy, less than 30% of these patients survive 5 years after diagnosis.1 The origin and pathogenesis of epithelial ovarian cancer, which accounts for 80% to 90% of all ovarian malignancies is still controversial. The most common histological type of epithelial ovarian cancer is serous papillary (55% to 60%). Less common subtypes are endometrioid, clear cell, mucinous, and undifferentiated. There is accumulating evidence that high-grade serous ovarian cancer does not originate from the ovarian surface epithelium but arises in the fimbrial epithelium of the fallopian tube, which secondarily implants to the ovary.2,3 Epithelial ovarian tumors exhibit a considerable intratumoral heterogeneity, where the final pathological classification of the tumor depends on the predominant histological characteristics of the specimen. Thus, the histological subtypes represent not distinct sub-groups but rather overlapping entities. Molecular pathways such as the Wnt or Hedgehog (Hh) signaling pathways participate in and propagate many phys-iologic developmental events in normal embryogenesis, as differentiation and proliferation are known to lead to tumor formation when aberrantly activated. Wnt and Hh signaling is active in many cancers.4 The Wnt pathway has been well studied in a number of cancers, where β-catenin mutations could be identified, no-tably colorectal cancer.5 In ovarian carcinoma, however, the detection of a high-rate (approximately 40%) of β-catenin mutations was confined to the endometrioid subtype of epithelial ovarian cancer.6-8 Further studies of this subtype showed that the fibroblast growth factor 9 (FGF9) was sig-nificantly overexpressed in the endometrioid ovarian cancer specimens that carried Wnt/β-catenin pathway deregulations.9 Axis inhibition protein 2 (AXIN2) is a negative regulator of the Wnt/β-catenin pathway and functions by participating in a negative feedback loop to limit the duration and intensity of a Wnt initiated signal. This effect is demonstrated in some solid tumors such as colorectal carcinoma, colorectal and liver tumors, craniopharyngiomas, hepatoblastoma, and rare pancreatic tumors. Little is known about the expression level of AXIN2 in ovarian cancer. Sonic hedgehog (SHH) and Indian HH (IHH) are se-creted proteins in the Hh pathway. Sonic hedgehog functions by binding and inactivating its receptor proteins, patched homolog 1 (PTCH-1) and PTCH-2 on target cells. Patched homolog 1 (and, possibly, PTCH-2), inhibits signaling through a physical interaction with a 7-span transmembrane protein, Smoothened (SMO), a signal transducer (or oncogene). On Hh ligand binding to PTCH, repression of SMO is abolished and signals are transduced through several kinases to the nucleus, which activates the GLI transcription factors.10 Hedgehog signaling pathway was shown to be associated with the tumorigenesis of basal cell, pancreas, prostate, digestive tract, glioma, and non–small cell lung cancers.11 Recently, data implicated the Hh pathway in ovarian cancer.12-14 However, the data are inconsistent, and more research is clearly needed. Yauch et al15 described a paracrine requirement for Hh signaling in the development of Hh-dependent tumor growth. Now there is evidence for an intrin-sic intratumoral and extrinsic microenvironment Hh signaling. In this report, we studied the activation of Wnt-related and Hh signaling genes in 16 primary grade 3 International Federation of Gynecology and Obstetrics (FIGO) stage III serous papillary ovarian tumors. For the Wnt pathway level, we looked at the expression of AXIN2 (negative feedback) and FGF9, which may function as a downstream growth factor in tumors. The Hh pathway activation was studied by the gene expressions of glioma-associated oncogene 1 (GLI1), GLI2, SMO, PTCH1, PTCH2, IHH, and SHH.