The cancer stem cell (CSC) hypothesis proposes that only the CSCs within a tumor possess the ability to self-renew and to generate new tumors. Under this model, CSCs are presumed responsible for cellular invasion and metastasis, as well as the recurrence of cancers following chemotherapy. In head and neck squamous cell carcinoma (HNSCC), cells which are CD44 positive and lineage negative (CD44+/Lin-) have been shown to possess properties of CSCs. These cells form tumors in NOD/SCID mice at a much greater efficiency compared to CD44-/Lin- cells, and express the proto-oncogene BMI-1. More recently, it has been shown in pancreatic cancer that a distinct subpopulation of CSCs expressing the chemokine receptor CXCR4 is essential for tumor metastasis. Here we demonstrate the existence of a highly invasive CXCR4+ subpopulation in HNSCC cancer stem cells and elucidate the pathways through which this subpopulation could be regulated.

For this study putative CSC cultures derived from primary HNSCC tissue were used from which CXCR4-expressing subpopulations were isolated. A matrigel invasion assay revealed that the CXCR4+ fraction of CSCs was significantly more invasive compared to the CXCR4- fraction. We also surveyed the mRNA expression of these two fractions by qRT-PCR, and found that expression of the proteinases MMP2 and MMP9 was markedly higher in CXCR4+ cells. Interestingly, treatment with nicotine increased the expression of CXCR4 and its ligand SDF-1 in the parental CSC culture, suggesting a possible mechanism by which CXCR4 could be regulated within the CSC population. Nicotine, a major component of tobacco, is known to have proliferative, anti-apoptotic, and angiogenic effects, and has been shown to promote epithelial-to-mesenchymal transition in a variety of human cancers.

Mortality from HNSCC remains high due primarily to cancer invasion of vital structures and development of distant metastases. Our findings shed light on the mechanisms by which CXCR4 confers an invasive and metastatic CSC phenotype. In addition, the observed effects of nicotine could provide novel insights towards the regulation of the CXCR4/SDF-1 axis in HNSCC, for which tobacco use has been identified as the leading risk factor. Continued efforts in mapping the molecular mechanisms surrounding CXCR4-mediated invasion and metastasis of CSCs could lead to new and effective treatment strategies for HNSCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4262.