The biology of ovarian cancer: new opportunities for translation

Abstract

Over the past two decades, the 5-year survival for ovarian cancer patients has substantially improved owing to more effective surgery and treatment with empirically optimized combinations of cytotoxic drugs, but the overall cure rate remains approximately 30%. Many investigators think that further empirical trials using combinations of conventional agents are likely to produce only modest incremental improvements in outcome. Given the heterogeneity of this disease, increases in longterm survival might be achieved by translating recent insights at the molecular and cellular levels to personalize individual strategies for treatment and to optimize early detection.• Several factors make ovarian cancer a difficult disease to treat effectively. Although many patients experience symptoms, these often overlap with other ailments, and many patients are diagnosed after the cancer has metastasized. Ovarian cancer is also heterogeneous -multiple genetic and epigenetic changes are evident in patients with ovarian cancer; however, how such changes are selected for during tumorigenesis is not yet clear.• Mutation and loss of TP53 function is one of the most frequent genetic abnormalities in ovarian cancer and is observed in 60-80% of both sporadic and familial cases. Of the 16 candidate tumour suppressor genes identified to date in ovarian cancer, 3 are imprinted genes. Several growth inhibitory genes are also silenced by methylation or imprinting.• Inheritance of DNA repair defects contributes to as many as 10-15% of ovarian cancers. The lifetime risk of developing ovarian cancer in mutation carriers varies with the genetic defect (for BRCA1 30-60%, for BRCA2 15-30% and for hereditary non-polyposis colon cancer 7%).• At least 15 oncogenes have been implicated in ovarian cancers, and DNA copy number abnormalities have also been found in loci that are known to contain noncoding microRNAs. At least seven signalling pathways are activated in >50% of ovarian cancers, and mutations that affect cell proliferation, apoptosis and autophagy are also evident.• Ovarian cancer can be split into two groups on the basis of genetic changes: low-grade tumours with mutations in KRAS, BRAF and PIK3CA, loss of heterozygosity (LOH) on chromosome Xq, microsatellite instability and expression of amphiregulin; and high-grade tumours with aberrations in TP53 and potential aberrations in BRCA1 and BRCA2, as well as LOH on chromosomes 7q and 9p.Correspondence to: Robert C. Bast, Jr 1 rbast@mdanderson.org. Competing interests statementThe authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Rev Cancer. Author manuscript; available in PMC 2010 February 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript• Changes in cell adhesion and motility also contribute to disease development and metastasis. Adhesion of ovarian cancer cells to the mesothelial cells and to the underlying stroma is mediated by CD44, CA125 and b1 intergrin on the surface of ovarian cancer cells that bind to mesotheli...

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

“…This is mediated at least in part through p53 activation and G2 arrest (G2/M checkpoint). It is therefore significant that up to 70% of all ovarian cancers 47 and over 90% of high-grade serous ovarian cancers 48 carry mutations in p53, which is also true for most of the cell lines studied here. Thus, the futile attempt to undergo mitosis may contribute to the selectivity of the carboplatin/ganetespib drug combination for cancer versus normal cells.…”

Vasohibin-2 Expressed in Human Serous Ovarian Adenocarcinoma Accelerates Tumor Growth by Promoting Angiogenesis

“…Ovarian cancer is the second most common malignant tumor in gynecology and is the leading cause of cancerrelated death for women worldwide (1). Cytotoxic therapy with platinum and taxanes is initially effective in many cases of ovarian cancer, but there is a considerable risk of recurrence and resistance to such cytotoxic therapy (2).…”

“…Ovarian cancer cells express various angiogenesis stimulators (1). Among them, VEGF plays the most important role, as it stimulates the migration and proliferation of, and tube formation by, endothelial cells.…”

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

“…Over 70% of EOC patients present with late stage diseases and dissemination of tumor implants throughout the peritoneal cavity (Bast et al, 2009). Ascites is one of the most common and distressing complications associated with EOC, especially for advanced stage diseases (Auersperg et al, 2002).…”