These observations have opened the possibility to revise the theory on the origin of ovarian cancer; it is plausible that the initial lesion might not be of ovarian origin but a metastasis of abnormal or transformed cells from different sites in the peritoneum. What these cells are and how they reach the ovaries are two main questions Inhibitors,research,lifescience,medical that need to be addressed and which will be examined in this review. HETEROGENEITY OF CANCER

CLONES The classical or clonal model to explain tumor formation and progression suggests that a tumor originates from a single mutated cell that is no longer under normal cell cycle control and thus divides incessantly. The constantly dividing cell forms a mass of identical fast-dividing cells, which results in a tumor. However, while this classical clonal Inhibitors,research,lifescience,medical KPT-330 concentration paradigm indeed exists, it provides a partial description of the biology of the tumor. Increasing evidence suggests that the

tumor is more complex; indeed it has been shown that there is a hierarchy Inhibitors,research,lifescience,medical in the cancer cells, where progenitor cancer stem cells, also known as tumor-initiating cells, can produce two or more distinct cell types. When we evaluated the cellular composition of epithelial ovarian tumors we were able to identify at least two distinct subtypes of ovarian cancer cells: the classical cancer cells, characterized by small size and fast cell division which we refer to as type II ovarian cancer cells; and the type I ovarian cancer cells, with different morphological characteristics and distinctive behavior (Figure 2). The type I cells are slowly dividing Inhibitors,research,lifescience,medical cells and share many markers with pluripotent stem cells. These markers include CD44, MyD88, ALDH1, and

others, which the smaller, rapidly dividing subtype lacks. Type I cells can Inhibitors,research,lifescience,medical rebuild the original tumor in mice (tumor-initiation potential), give origin to CD44-negative/MyD88-negative type II cells (differentiation capacity), serve as tumor vascular progenitors (pluripotency), and are chemoresistant.14–18 Indeed, levels of type I cells are associated with shorter progression-free survival in ovarian cancer patients.18 Our findings are in line with other studies that have shown the existence of tumor-initiating cells in ovarian below cancer through the use of different markers suggestive of the heterogeneity of the disease.14,19–23 Figure 2 Two distinct cell types in an ovarian tumor. An important characteristic of type I cells is their potential to give origin to the fast-dividing type II cells. This aspect was demonstrated in our animal studies where only CD44-positive cells are able to form tumors in nude mice. Once the tumor was established, we evaluated the cellular composition of the tumors. If the clonal hypothesis had been correct, the tumor would have been comprised of only CD44-positive cells.