Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance

TLDR

Ovarian cancer treatment is hampered by high recurrence and chemoresistance, largely driven by cancer stem cells that self‑renew, generate bulk tumor cells, and possess molecular traits that promote self‑renewal and metastasis. The study aims to characterize and clone human ovarian cancer stem cells to inform the development of improved therapeutic strategies. The identified OCSCs exhibit a distinctive genetic profile (CD44+, MyD88+, constitutive NFκB activity, cytokine/chemokine production) that confers tumor recapitulation, chemoresistance, high repair capacity, and resistance to apoptosis, enabling them to survive chemotherapy and drive recurrence.

Abstract

A major burden in the treatment of ovarian cancer is the high percentage of recurrence and chemoresistance. Cancer stem cells (CSCs) provide a reservoir of cells that can self-renew, can maintain the tumor by generating differentiated cells [non-stem cells (non-CSCs)] which make up the bulk of the tumor and may be the primary source of recurrence. We describe the characterization of human ovarian cancer stem cells (OCSCs). These cells have a distinctive genetic profile that confers them with the capacity to recapitulate the original tumor, proliferate with chemotherapy, and promote recurrence. CSC identified in EOC cells isolated form ascites and solid tumors are characterized by: CD44+, MyD88+, constitutive NFκB activity and cytokine and chemokine production, high capacity for repair, chemoresistance to conventional chemotherapies, resistance to TNFα-mediated apoptosis, capacity to form spheroids in suspension, and the ability to recapitulate in vivo the original tumor.Chemotherapy eliminates the bulk of the tumor but it leaves a core of cancer cells with high capacity for repair and renewal. The molecular properties identified in these cells may explain some of the unique characteristics of CSCs that control self-renewal and drive metastasis. The identification and cloning of human OCSCs can aid in the development of better therapeutic approaches for ovarian cancer patients.