Abstract
The aim of the study was to investigate cancer stem signaling during the repopulation response of a head and neck squamous cell cancer (HNSCC) xenograft after radiation treatment. Xenografts were generated from low passage HNSCC cells and were treated with either sham radiation or 15 Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21, after irradiation, 3 tumors per group were harvested for global gene expression, pathway analysis, and immunohistochemical evaluation. 316 genes were identified that were associated with a series of stem cell-related genes and were differentially expressed (p ≤ 0.01 and 1.5-fold) at a minimum of one time point in UT-SCC-14 xenografts after radiation. The largest network of genes that showed significant changes after irradiation was associated with CD44, NOTCH1, and MET. c-MET and ALDH1A3 staining correlated with the changes in gene expression. A clear pattern emerged that was consistent with the growth inhibition data in that genes associated with stem cell pathways were most active at day 7 and day 12 after irradiation. The MET/CD44 axis seemed to be an important component of the repopulation response.
Highlights
Head and neck squamous cell cancers (HNSCCs) are a heterogeneous group of malignancies that originate in the mucosal lining of the upper aerodigestive tract
We developed a model of local failure and repopulation in a HNSCC xenograft using a subcurative dose of radiation and studied the changes in protein expression of known stem cell-related genes as well as stem cell-related signaling pathways using global gene expression at key time points during the tumor response
We developed a model which interrogated the molecular changes associated with known stem cell linked genes during the repopulation/regrowth of a HNSCC xenograft after a subcurative radiation treatment
Summary
Head and neck squamous cell cancers (HNSCCs) are a heterogeneous group of malignancies that originate in the mucosal lining of the upper aerodigestive tract. There is an increasing awareness that not all heterogeneity among cancer cells is the result of genetic variability and that, within a single tumor clone, cells have significantly different abilities to proliferate and form new tumors. This has led to the hypothesis that most cells in a cancer have a limited ability to divide and only a small subset of phenotypically distinct cells, the cancer stem cells (CSCs), have the capacity to self-renew and form new tumors [5]. The presence of cells with “stem-like” properties has been observed in HNSCC using a variety of different approaches [6,7,8,9,10,11]
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