Microenvironment and pathogenesis of epithelial ovarian cancer

Abstract

Multiple genetic alterations play a role in the pathogenesis of ovarian cancer. Although many key proteins and pathways involved in ovarian carcinogenesis and metastasis have been discovered, knowledge of the early steps leading to malignancy remains poorly understood. This poor understanding stems from lack of data from early-stage cancers and absence of a well-established premalignant state universal to all ovarian cancer subtypes. Existing evidence suggests that ovarian cancers develop either through a stepwise mutation process (low-grade pathway), through genetic instability resulting in hastened metastasis (high-grade pathway), or more recently through what has been described as the "'fimbrial-ovarian' serous neoplasia theory." In this latter model, ovarian serous cancers evolve from premalignant lesions in the distal fallopian tube called tubal intraepithelial carcinoma. In this manuscript, we review key genetic and molecular changes that occur in cancer cell progression and suggest a model of ovarian cancer pathogenesis involving both tumor cell mutations and microenvironmental factors.

Fig. 1

Proposed model of ovarian carcinogenesis (adapted from JCO 2008:995–1005 (Feb 20) with permission). Normal ovarian epithelium is exposed to physiologic processes that may predispose to malignant transformation, such as prolonged androgen exposure. A number of characteristics must be obtained, primarily through mutations or other genetic changes, to be transformed to a malignant state. These include unregulated growth, resistance to anti-growth signals, inhibition of apoptosis, evasion of recognition by the immune system, achieving limitless replicative potential, induction of angiogenesis, and invasion of the basement membrane. Examples of specific proteins known to play a role in each of these processes in ovarian cancer are listed in italics. The order in which these mutations may occur is not well understood, but the timing and specific protein affected may be significant in producing different histological subtypes and grades of ovarian cancer. For example, if mutations favoring growth and resistance to apoptosis occurred early, prior to achieving the potential for invasion and metastasis, an intermediate pathologic subtype would be noted more often, such as k-ras mutations in LMP tumors. A mutation leading to genetic instability, such as p53, that occurred early would predispose cells to other mutations and rapid progression to a metastatic phenotype, as seen in high-grade malignancies. Permissive or contributing factors of the microenvironment, such as production of MMPs by fibroblasts (pictured in red), infiltration of inflammatory cells (pictured in blue), and proliferation of endothelial cells for angiogenesis, may be just as important as mutations in the tumor cells