Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

Abstract

Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed ‘CSC niche’, where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.

Antitumor Efficacy of the Herbal Recipe Benja Amarit against Highly Invasive Cholangiocarcinoma by Inducing Apoptosis both In Vitro and In Vivo

“…Chemotherapy is recommended for more than 70% of patients with cholangiocarcinoma (CCA) due to the frequently late diagnosis that is associated with this disease [9]. However, CCA is able to evade chemotherapy by powerful mechanisms of chemoresistance [7,8], which means that its response to available chemotherapeutic agents is very low [31,32]. In this research study, we have discovered a novel effective alternative treatment for CCA involving the herbal recipe Benja Amarit (BJA).…”

Evolution of the Experimental Models of Cholangiocarcinoma

“…In another study, spheroids were established from the iCCA cell lines SG231, HUCCT1, CCLP1, and CCA4; their molecular characterization revealed an increased expression of key genes involved in pluripotency, self-renewal, drug-resistance, and survival, as well as stem-like surface markers [122]. Indeed, CCA spheroid (cholangiosphere) models, like those from other tumors, are characterized by the presence of putative CSC and by enhanced tumorigenicity in xenograft models [71] and chemoresistance [123,124]. However, CSC markers specific of CCA have not been extensively studied; immunophenotypic analysis showed the expression of canonical CSC markers (CD133, CD24, CD44, EpCAM, Sox2, Nanog, OCT3/4, CD49f, CD11, FoxA 1/2, PDX1, Sox17, CK7/19) [123,125].…”

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

“…Furthermore, several studies have shown that purified CD133 + cells from HCC cell lines have higher proliferation potential and tumorigenic ability in animal models and exhibit stem cell-like characteristics, including their ability to self-renew and differentiate into multiple cell lineages [ 10 ]. Moreover, a subset of ICCs expresses stem/progenitor cell-related markers, suggesting CSCs are a possible cell source for ICC [ 11 , 12 , 13 , 14 ]. Thus, identifying and selectively targeting CSCs represents a feasible therapeutic strategy for treating liver cancer regardless of the underlying cause.…”