Abstract
Recently, cancer stem cells (CSC), undifferentiated cancer progenitor cells, have been successfully isolated from colorectal tumors. Targeting both CSCs and differentiated, rapidly proliferating tumor cells with therapeutic drugs provides a focused strategy to treat cancer. In this study, we isolated the monoclonal antibody (mAb) CC188 and characterized the epitope recognized by mAb CC188, which is useful for developing biological reagents that target CSCs. We used a hybridoma technique to generate mAbs and an immunomagnetic method to isolate colon CSCs. We characterized mAb CC188 binding epitope and examined the epitope distribution in normal and tumor tissues, particularly in CSCs using tissue arrays and immunofluorescence staining method. We also evaluated the effect of mAb CC188 on invasiveness of NSY tumor cells. mAb CC188 was generated and 98.9% (187 of 189 cases) of colon cancer were positively stained by mAb CC188. "+", "++," and "+++" staining were 25.9%, 28.6%, and 43.4%, respectively. The mAb CC188 binding epitope was identified as a carbohydrate, which was expressed on the surface of colon CSCs (CD133+), differentiated colon cancer cells (CD133-), and cells from various types of epithelial tumors. In contrast, the expression of the carbohydrate epitope was low in normal prostate muscle and pancreatic acinar cells, as well as in some normal epithelial cells of the breast duct, cervix, and skin. A functional study indicated that mAb CC188 suppressed the invasiveness of NSY tumor cells. mAb CC188 selectively targets a carbohydrate epitope expressed on cancer cells, providing a viable method for specific tumor imaging and targeted therapy.
Highlights
Colorectal tumor is the third most common form of cancer worldwide [1], with estimated 153,760 new cases and 52,180 deaths in the United States alone in 2007.5 Improvement of cancer diagnosis and discovery of novel therapeutic approaches are essential to fight the disease
Toward the goal of eradicating primary and metastatic tumors in humans, we have generated a monoclonal antibody designated as mAb CC188, which selectively targets a carbohydrate epitope expressed on cancer stem cells (CSC) and differentiated cancer cells
We generated a monoclonal antibody designated as mAb CC188 by screening hybridoma libraries
Summary
Colorectal tumor is the third most common form of cancer worldwide [1], with estimated 153,760 new cases and 52,180 deaths in the United States alone in 2007.5 Improvement of cancer diagnosis and discovery of novel therapeutic approaches are essential to fight the disease. Recent studies have shown that cancer stem cells (CSC) can self-renew and differentiate into mature diversified cancer cells and are responsible for tumor initiation, growth, and metastasis (2 – 5). A number of these tumor-associated epitopes are normally cryptic antigens and become exposed after incomplete glycosylation that occurs frequently in malignant cells It is unknown whether these epitopes are expressed in CSCs. Currently, many research efforts have focused on identifying biomarkers that are expressed in CSCs and absent in normal stem cells and their differentiated progeny normal cells. A functional study indicated that the epitope suppressed the invasiveness of NSY colon tumor cells Based on these findings, we envisage the use of mAb CC188 in humans as a carrier for specific delivery of imaging agents and chemotherapeutic drugs to both CSCs and differentiated tumor cells. Considering that mAb CC188 has an intrinsic ability to suppress invasiveness of colon cancer cells, coupling it with a chemotherapeutic drug could provide an effective therapeutic regimen for the eventual eradication of the devastating disease
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