Authors:
Gil Mor, Rui Chen, Han Hsuan Fu, Michele Montagna, Irene Visintin, Dan Silasi, Peter Schwartz, Masoud Azodi, Thomas Rutherford, Ayesha Alvero
Summary:
Introduction - One of the major burdens in the treatment of epithelial ovarian cancer (EOC) is the high percentage of recurrence characterized by chemoresistance. The biology underlying the tumor’s high capacity for recurrence has not been elucidated. Tumors are made of a heterogeneous cell population consisting of both cancer and non-cancer cells. New data suggest that even the cancer cell population is heterogeneous and contains a small subset of cells, the cancer stem cells (CSC), which constitute a reservoir that can self-renew and therefore maintain the tumor. CSC can divide and expand their pool and also differentiate into non-CSC, which constitute the bulk of the tumor. Contrary to CSC, the non-CSC are rapidly dividing and therefore sensitive to therapies, which target highly proliferative cells. In the present study we identified and characterized the CSC of EOC.
Methods - EOC cells were isolated from malignant ovarian cancer ascities and solid tumors (n=80). Marker expression was determined using Flow Cytometry, Western Blots and Immunocytochemistry. Xenograft nude mice model was used for tumor growth by injecting cancer cells either s.c. or i.p. Isolation of CD44+ population was done using FACS. Cancer cells were maintained in culture as previously described {Kamsteeg, 2003 #358}
Results - CSC were identified in EOC cells isolated form ascites and solid tumors with the following characteristics: 1) cellular markers: 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 unique microRNA phenotype; 2) tumor formation in animals: 100% CD44+ cells formed tumors which contained 10% CD44+ and 90% CD44-negative cells. Re-injection of isolated CD44+ cells from previous engraftment was able to again recapitulate the original tumor phenotype. Isolation and in vitro treatment of CD44+ cells from fresh samples showed resistance to carboplatin and paclitaxel. In contrast, the sorted CD44-negative cell population from the same sample/patient was chemosensitive.
Conclusion - Present chemotherapy modalities eliminate the bulk of the tumor but it leaves a core of cancer cells with high capacity for repair and renewal. CSC corresponds to the core of malignant cells that promotes recurrence and chemoresistance. Identification of these cells represents the first step in the development of therapeutic modalities that can eliminate not only the bulk of the tumor but its source. Prevention of recurrence will be achieved only with therapies targeting this cell population.
Source:
American Association of Cancer Research (AACR); Exhibit Hall B-F, San Diego Convention Center, (04/14/08)