Abstract
Identification of novel biomarkers for tumor-initiating cells (TICs) is of critical importance for developing diagnostic and therapeutic strategies against cancers. Here we identified the role of KIAA1114, a full-length translational product of the trophinin gene, as a distinctive marker for TICs in human liver cancer by developing a DNA vaccine-induced monoclonal antibody targeting the putative extracellular domain of KIAA1114. Compared with other established markers of liver TICs, KIAA1114 was unique in that its expression was detected in both alpha fetoprotein (AFP)-positive and AFP-negative hepatocellular carcinoma (HCC) cell lines with the expression levels of KIAA1114 being positively correlated to their tumorigenic potentials. Notably, KIAA1114 expression was strongly detected in primary hepatic tumor, but neither in the adjacent non-tumorous tissue from the same patient nor normal liver tissue. KIAA1114high cells isolated from HCC cell lines displayed TIC-like features with superior functional and phenotypic traits compared to their KIAA1114low counterparts, including tumorigenic abilities in xenotransplantation model, in vitro colony- and spheroid-forming capabilities, expression of stemness-associated genes, and migratory capacity. Our findings not only address the value of a novel antigen, KIAA1114, as a potential diagnostic factor of human liver cancer, but also as an independent biomarker for identifying TIC populations that could be broadly applied to the heterogeneous HCC subtypes.
Highlights
Durable complete remission has been rarely achieved with conventional anticancer strategies owing to sustained survival or continuous reappearance of therapy-resistant tumor cells that cause locoregional relapse and distant metastasis
We proposed the role of a novel tumor-associated antigen, KIAA1114, as a bona fide marker for liver cancer stem cells (CSCs), based on the functional and phenotypic features displayed by isolated KIAA1114high hepatocellular carcinoma (HCC) in several CSC assays
Anchorage-dependent colony formation assay revealed that KIAA1114high cells derived from both alpha fetoprotein (AFP)+ and AFP− cell lines retained superior proliferative capacities than KIAA1114low cells
Summary
Durable complete remission has been rarely achieved with conventional anticancer strategies owing to sustained survival or continuous reappearance of therapy-resistant tumor cells that cause locoregional relapse and distant metastasis. Such observation led to the emergence of “cancer stem cell” hypothesis that tumors, like normal somatic tissues, contain distinct stem celllike populations having strong regeneration capacity and drug resistance. The exact definition of “cancer stem cells (CSCs)” was recently provided by Valent et al that CSCs are a subset of neoplastic stem cells that drives indefinite proliferation of malignant clones and production of an apparent cancer [1] They suggested that the term “tumor-initiating cells (TICs)”, which has been widely used to describe experimentally identified CSCs, may be applied to characterize cells that are capable of initiating the formation of a detectable, continuously growing tumor in xenograft models [1]. Despite the comprehensive list of CSC markers, clinical transition of most available markers has been rarely achieved since the application of a sole marker for broad range of tumor subtypes has been frequently hampered by intertumoral and intratumoral heterogeneity of a given cancer
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