could have contributed to the changes survival of cells at the centre of the multicellular aggregates, since mathem atical modeling suggests that deficiencies in ATP, glucose, hydrogen and oxygen may all induce nec rotic cell death of cells within spheroid cores. Many key cellular processes are now known to be dif ferently regulated between 2D and 3D cultures, and vari ous factors can induce differential gene expression in 3D, including altered cell cell and or cell matrix commu nications, nutrient and oxygen gradients, and reduced rates of proliferation. We propose that the 3D models are more biologically relevant tools of FTSECs than trad itional 2D monolayers with which to study fallopian tube epithelial cell biology and pathogenesis.
Perhaps the greatest potential for clinical impact of these models will come from their use in studies of tumor initiation. This has become particularly significant since it Cilengitide was established recently that the epithelia lining of the fallopian tube likely represents the cell of origin for a proportion of HGSOCs. HGSOCs bear morphological resemblance to M��llerian epithelia and over 80% of this tumor type overexpress PAX8, an FTSEC marker that can be used to distin guish ovarian serous tumors from other, morphologically similar neoplasms. We identified additional FTSEC biomarkers that represent novel candidate HGSOC bio markers. These include LRRK2, a gene that encodes a kin ase involved in Parkinsons Disease. LRRK2 has not previously been implicated in ovarian cancer development but analyses of The Cancer Genome Atlas data suggests 3% of primary HGSOCs harbor somatic muta tions in this gene.
Other novel FTSEC biomarkers that are overexpressed in HGSOCs include CELSR3, an atypical cadherin, ABCC3, an ABC transport protein im plicated in drug resistance, and CTHRC1, a secreted protein shown to be a candidate biomarker for breast and pancreatic cancer. Analyses of primary HGSOC specimens and sera collected from ovarian can cer patients will be required to determine whether any of these novel biomarkers have clinical utility in the early detection of HGSOC. While it is now widely accepted that a proportion of HGSOCS originate in the fallopian tube, the early stages of disease development are poorly understood and many questions remain to be answered.
Reports show differ ences in the proportions of ciliated and secretory epithelial cells, marker expression and hormone respon siveness between the epithelia found in fimbrial and ampullary regions of the fallopian tube. How ever, as yet we do not yet know why FTSECs in the fim brial region of the fallopian tube are more prone to neoplastic transformation. One hypothesis is that the proximity to the mitogenic environment of the ovarian stroma may influence the phenotype of fimbrial FTSECs. Alternatively the region of transition between FTSECs and ovarian mesothelial type epithelial cells is inherently more prone to neoplastic transformation. In the future, these 3D models of