Cancer stem cells have recently been proposed to be the cancer initiating cells that are responsible for tumorigenesis and for contributing to cancer resistance in leukemia[11
]. Compared to leukemia, evidence for the existence of cancer stem cells in solid tumors has been more difficult to obtain for several reasons. Cells within solid tumors are less accessible, and functional assays suitable for detecting and quantifying normal stem cells from many organs have not yet been developed, and the cell surface markers required to isolate such cells have not been identified fully. However, there have been some impressive studies in this area recently. Advances have been made in identifying and enriching cancer stem cells in several solid tumors, including breast, brain and colon cancers[4–10
Lapidot et al[12
] have shown that leukemia-initiating stem cells present in the peripheral blood of acute myelogenous leukemia (AML) patients can induce AML when transplanted into severe combined immunodeficient mice. In 2003, Al-Hajj et al[8
] isolated human breast cancer stem cells that can cause breast cancer in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice through serial transplantations, which suggests a capacity for self-renewal. The following year, Singh et al[6
] have found evidence of stem cell involvement in brain cancer. Recently, O’Brien et al[4
] have demonstrated that CD133-positive colon-cancer-initiating cells in the human colon cancer specimen generate tumors in the renal capsule of pre-irradiated NOD/SCID mice. More recently, cells have been isolated from human prostate cancer patients, which can produce serially transplantable prostate tumors in NOD/SCID mice[10
]. Even though definitive cancer stem cell markers have not been found in all the previously mentioned studies, these studies have revealed that only a small subset of cells in different tumor types is capable of tumor formation and several candidate stem cell markers have been evaluated. While CD133, CD24 and CD44 have been tested as cancer stem cell markers for serial transplantation studies in various cancers, their prognostic value has not been elucidated clearly[4–10
CD133, which is one of the most important cancer stem cell markers[4–7
], was stained fairly well in 24.5% of our colon cancer patients. In terms of clinicopathological parameters, CD133 expression was related to gender and T stage. The present study revealed that male gender was positively related to CD133 expression. T0 and T1 colon cancers showed lower incidence of CD133 protein expression compared to advanced colon cancer.
CD24, another important cancer stem cell marker, was expressed in 50.5% of the colon cancer patients. Correlation between CD24 expression and clinicopathological factors was seen in degree of differentiation. CD24 consists of a small protein core comprising 27 amino acids, which is extensively glycosylated and is bound to the membrane via a phosphatidylinositol anchor[13–15
]. Several reports have shown that CD24 can be expressed on several solid tumors such as small cell lung cancer, neuroblastoma, rhabdomyosarcoma and renal cell cancer[16,17
]. Lim et al[18
] have reported that CD24 expression is related to lymph node metastasis in colon cancer. Weichert et al[19
] have shown that cytoplasmic CD24 expression in colorectal cancer is independently correlated with shortened patient survival. We have not seen any positive correlation between CD24 expression and nodal status and patient survival.
CD44 is an unique adhesion molecule and several studies have revealed that CD44 is overexpressed at the mRNA and protein levels in colon cancer[20,21
]. In our study, large tumors bigger than 5.5 cm showed more frequent CD44 expression, which indicated that CD44 expression was related to clinical tumor burden.
Our results in human colon cancer specimens showed various expression patterns of CD markers. This is believed to be the first trial to verify the relationship between well-known prognostic factors of colon cancer and conventional cancer stem cell markers. Tumor invasiveness and differentiation were identified as clinicopathological factors related to cancer stem cell markers, especially CD133 and CD24.
For further study, other colon stem cell markers which are related to patient survival should be found for clinical application of colon cancer stem cells. Several studies have indicated that pleuripotency-related factors, including Oct3/4, are related to cancer development[22–24
]. Beside CD markers, other cancer stem cell markers may help distinguish cancer stem cells from cancer cells.
In summary, we have presented some evidence that several conventional clinical factors were related to cancer stem cell markers in colorectal adenocarcinoma. However, CD133, CD24 and CD44 expression did not show a close relationship with the survival outcome of colorectal adenocarcinoma. These results warrant further careful and well-designed studies of colon cancer stem cells as markers for clinical application.