Induction of metastatic cancer stem cells from the NK/LAK-resistant floating, but not adherent, subset of the UP-LN1 carcinoma cell line by IFN-γ

• Published in: Laboratory investigation Vol. 91; no. 10; pp. 1502 - 1513
• Main Authors: Chen, Hung-Chang, Chou, Andy Shau-Bin, Liu, Yu-Chen, Hsieh, Chin-Hsuan, Kang, Chen-Chen, Pang, See-Tong, Yeh, Chi-Tai, Liu, Hui-Ping, Liao, Shuen-Kuei
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2011; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Biotechnology; Carcinoembryonic Antigen - metabolism; Carcinogenicity Tests; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma - secondary; CD24 Antigen - metabolism; CD44/CD24; Cell Line, Tumor; Chemokine CXCL12 - metabolism; CXCR4/CXCL12 axis; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression; Histocompatibility Antigens Class I - metabolism; HLA class I; Humans; Hyaluronan Receptors - metabolism; Immunophenotyping; Interferon-gamma - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Killer Cells, Lymphokine-Activated - drug effects; Killer Cells, Lymphokine-Activated - metabolism; Lymphatic Metastasis; Medical sciences; metastasis; metastatic cancer stem cells; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; non-MHC-restricted effector lymphocytes; Receptors, CXCR4 - metabolism; Transplantation, Heterologous; metastatic cancer stem cells; CXCR4/CXCL12 axis; HLA class I; metastasis; non-MHC-restricted effector lymphocytes; CD44/CD24; Transmembrane protein; Carcinoma; Induction; Stem cell; Cell adhesion molecule; Malignant tumor; Metastasis; Natural killer cell; Resistance; Cell line; Established cell line; T-Lymphocyte; Advanced stage; Metastatic; CXC chemokine; Tumor cell; Cancer; Gamma interferon; Biological receptor
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2011.91

As an advanced status of cancer stem cells (CSCs), metastatic CSCs (mCSCs) have been proposed to be the essential seeds that initiate tumor metastasis. However, the biology of mCSCs is poorly understood. In this study, we used a lymph node (LN) metastatic CEA-producing carcinoma cell line, UP-LN1, characterized by the persistent appearance of adherent (A) and floating (F) cells in culture, to determine the distribution of CSCs and mechanisms for the induction of mCSCs. F and A cells displayed distinct phenotypes, CD44high/CD24low and CD44low/CD24high, respectively. The CSC-rich nature of F cells was typified by stronger expression of multiple drug resistance genes and a 7.8-fold higher frequency of tumor-initiating cells in NOD/SCID mice when compared with A cells. F cells showed a greater depression in HLA class I expression and an extreme resistance to NK/LAK-mediated cytolysis. Moreover, the NK/LAK-resistant F cells were highly susceptible to IFN-γ-mediated induction of surface CXCR4, with concomitant downregulation of cytoplasmic CXCL12 expression, whereas these two parameters remained essentially unchanged in NK/LAK-sensitive A cells. Following the induction of surface CXCR4, enhanced migratory/invasive potential of F cells was demonstrated by in vitro assays. Confocal immunofluorescence microscopy showed the two distinct phenotypes of F and A cells could be correspondingly identified in monodispersed and compact tumor cell areas within the patient's LN tumor lesion. In response to IFN-γ or activated NK/LAK cells, the CXCR4+ mCSCs could be only induced from the CSCs, which were harbored in the highly tumorigenic CD44high/CD24low F subset. Our results revealed the complexity and heterogeneity of the CSC of this cell line/tumor and the differential immunomodulatory roles of F and A cells. A better understanding of the interactions among different classes of CSCs and their niches may assist us in eradicating the CSCs/mCSCs through targeted immunotherapy, chemotherapy, or both.