Stem and Progenitor-Like Cells Contribute to the Aggressive Behavior of Human Epithelial Ovarian Cancer

Abstract

The cellular mechanisms underlying the increasing aggressiveness associated with ovarian cancer progression are poorly understood. Coupled with a lack of identification of specific markers that could aid early diagnoses, the disease becomes a major cause of cancer-related mortality in women. Here we present direct evidence that the aggressiveness of human ovarian cancer may be a result of transformation and dysfunction of stem cells in the ovary. A single tumorigenic clone was isolated among a mixed population of cells derived from the ascites of a patient with advanced ovarian cancer. During the course of the study, yet another clone underwent spontaneous transformation in culture, providing a model of disease progression. Both the transformed clones possess stem cell-like characteristics and differentiate to grow in an anchorage-independent manner in vitro as spheroids, although further maturation and tissue-specific differentiation was arrested. Significantly, tumors established from these clones in animal models are similar to those in the human disease in their histopathology and cell architecture. Furthermore, the tumorigenic clones, even on serial transplantation continue to establish tumors, thereby confirming their identity as tumor stem cells. These findings suggest that: (a) stem cell transformation can be the underlying cause of ovarian cancer and (b) continuing stochastic events of stem and progenitor cell transformation define the increasing aggression that is characteristically associated with the disease. (Cancer Res 2005; 65(8): 3025-9)

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

“…The existence of ovarian cancer-initiating cells was previously supported by others in studies whereby cancer cells isolated from ascitic fluid of ovarian cancer patients exhibited characteristics consistent with those expected of a cancer stem cell (Bapat et al, 2005;Szotek et al, 2006). More recently, CD44 þ ovarian cancer cells have been shown to possess cancer-initiating capabilities (Zhang et al, 2008).…”

Cancer stem cells as targets for cancer therapy: selected cancers as examples

“…In vivo, ovarian SP cells have the potential to initiate tumor growth more quickly and at lower cell numbers than non-SP ovarian cancer cells [165]. Moreover, cell clones with sustained clonogenic potential in vitro and tumorgenicity in vivo, even after serial transplantation in mice, have been identified in ovarian cancer [16]. The possible multipotency of such clones was further supported by the expression of three "stemness" markers: Oct4, Nanog, and Nestin [16].…”

“…Moreover, cell clones with sustained clonogenic potential in vitro and tumorgenicity in vivo, even after serial transplantation in mice, have been identified in ovarian cancer [16]. The possible multipotency of such clones was further supported by the expression of three "stemness" markers: Oct4, Nanog, and Nestin [16]. More recently, Ferrandina et al [50] identified the expression of CD133 antigen, considered to be a marker of undifferentiated cells, in a cellular subpopulation in a large variety of ovarian tissues.…”

Nuclear–mitochondrial genomic profiling reveals a pattern of evolution in epithelial ovarian tumor stem cells

“…In the second part of the study, we used an in vitro model developed earlier by us that comprises 19 single-cell clones isolated from the ascites of an ovarian serous adenocarcinoma patient (Bapat et al, 2005). Of these, one clone was tumorigenic (A2); another one (A4) underwent a spontaneous transformation in vitro, whereas the remaining 17 clones were non-tumorigenic.…”