The role of CD44 in progression of
head and neck squamous cell carcinoma (
HNSCC) has been controversial. The goal of this study was to study the effects of CD44(+)
tumor cells on the initial stages of
tumor angiogenesis and to evaluate CD44 as a potential marker of
tumor angiogenesis. The CD44 gene expression was studied using the
Cancer Genome Atlas (TCGA)
Head and Neck Cancer data base. Expression levels of CD44 and of microvascular density (MVD) markers were assessed by immunohistochemistry performed with tissue microarrays in a cohort of 49
HNSCC patients, 11 patients with dysplasia and 12 control oral mucosa tissues. The
4-nitroquinoline-1-oxide oral
carcinogenesis mouse model was used to study CD44 expression during
carcinogenesis.
Gelatin sponges seeded with CD44(+), CD44(-) and unsorted
cancer cells suspended in
Matrigel were implanted in NOD/SCID mice into a dorsal skinfold chamber and compared to non-seeded sponges as controls. Angiogenic response was assessed by intravital microscopy. In the TCGA analysis, CD44 gene expression correlated with various pro-angiogenic genes. In human
HNSCC tissues, CD44 expression was upregulated and was associated with blood vessels, although no correlation between MVD and CD44 expression was found. During oral
carcinogenesis CD44 expression was upregulated. In dorsal skinfold chambers, CD44(+) cells showed a significantly higher MVD than CD44(-) or unsorted cells (p < 0.001). The results indicate that CD44(+) cells contain pro-angiogenic factors and stimulate
tumor angiogenesis in
HNSCC. Thus, CD44 might emerge as a potential angiogenic
biomarker and a therapeutic target for anti-angiogenic
therapies.