CD133 expression in chemo-resistant Ewing sarcoma cells

Abstract

BackgroundSome human cancers demonstrate cellular hierarchies in which tumor-initiating cancer stem cells generate progeny cells with reduced tumorigenic potential. This cancer stem cell population is proposed to be a source of therapy-resistant and recurrent disease. Ewing sarcoma family tumors (ESFT) are highly aggressive cancers in which drug-resistant, relapsed disease remains a significant clinical problem. Recently, the cell surface protein CD133 was identified as a putative marker of tumor-initiating cells in ESFT. We evaluated ESFT tumors and cell lines to determine if high levels of CD133 are associated with drug resistance.MethodsExpression of the CD133-encoding PROM1 gene was determined by RT-PCR in ESFT tumors and cell lines. CD133 protein expression was assessed by western blot, FACS and/or immunostaining. Cell lines were FACS-sorted into CD133+ and CD133- fractions and proliferation, colony formation in soft agar, and in vivo tumorigenicity compared. Chemosensitivity was measured using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays.ResultsPROM1 expression was either absent or extremely low in most tumors. However, PROM1 was highly over-expressed in 4 of 48 cases. Two of the 4 patients with PROM1 over-expressing tumors rapidly succumbed to primary drug-resistant disease and two are long-term, event-free survivors. The expression of PROM1 in ESFT cell lines was similarly heterogeneous. The frequency of CD133+ cells ranged from 2-99% and, with one exception, no differences in the chemoresistance or tumorigenicity of CD133+ and CD133- cell fractions were detected. Importantly, however, the STA-ET-8.2 cell line was found to retain a cellular hierarchy in which relatively chemo-resistant, tumorigenic CD133+ cells gave rise to relatively chemo-sensitive, less tumorigenic, CD133- progeny.ConclusionsUp to 10% of ESFT express high levels of PROM1. In some tumors and cell lines the CD133+ fraction is relatively more drug-resistant, while in others there is no apparent difference between CD133+ and CD133- cells. These studies reveal heterogeneity in PROM1/CD133 expression in ESFT tumors and cell lines and confirm that high levels of PROM1 expression are, in at least some cases, associated with chemo-resistant disease. Further studies are required to elucidate the contribution of PROM1/CD133 expressing cells to therapeutic resistance in a large, prospective cohort of primary ESFT.

Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties

“…The mechanisms of the PDTresistance of the CD133 high population is unknown and should be further explored; however, recently it was shown that CD133 expression is correlated to both chemo-and radiation therapy resistance [39][40][41]. Interestingly, treating prostate cancer cells with short-term differentiation therapy resulted in enhanced photosensitisation of prostate cancer cells [42].…”

Ewing Sarcoma of the Jaws

“…There are other reports of Ewing sarcoma of the jaw bone initially misdiagnosed and treated as an odontogenic infection. 4,5 Ewing sarcoma and odontogenic abscess might have some common signs and symptoms including swelling, pain, loss of teeth vitality, increased C-reactive protein, leukocytosis, and elevated temperature. Therefore, in those seemingly odontogenic abscesses that do not respond to antibiotic therapy, particularly in the mandible of a young patient, Ewing sarcoma should be considered, and early incisional biopsy is recommended.…”

Formation of spherical cancer stem-like cell colonies with resistance to chemotherapy drugs in the human malignant fibrous histiocytoma NMFH-1 cell line

“…Previous studies have revealed that specific surface molecules, including cluster of differentiation (CD)133 and CD44, may be markers for certain CSC populations (8)(9)(10)(11). Several studies have indicated that CSCs may demonstrate the ability of increased resistance to chemotherapy, due to the high expression of specific drug transporters, including multidrug resistance protein 1 and adenosine triphosphate (ATP)-binding cassette (ABC) sub-family G member 2 (ABCG2) (12,13).…”

“…CD133 has been used as a marker for hematopoietic stem cells (43) and neuronal stem cells (44). Previously, various studies have demonstrated that CD133 is associated with the initiation and progression of cancer stem and progenitor cells, and may be a valuable CSC marker in a variety of tumors, including epithelial cancers and solid sarcomas (10,11,(45)(46)(47)(48)(49)(50). Therefore, the increased expression of CD44 and CD133 in NMFH-1 spherical colonies may account for the increased survival and metastatic ability of these cells.…”