Head and Neck Squamous Cell Carcinoma Progression and Chemoresistance. Part 5
CD44 v6-containing isoforms also appear to promote tumor progression. Transfection of CD44 v6 converted nonmetastatic rat carcinoma cells into metastatic cells, and co-injection of anti-CD44 v6 antibody into these same cells suppressed their metastatic behavior. The CD44 v6 splice variant was also found to stimulate sustained increased mitogen activated protein kinase (MAPK) levels and subsequent downstream Ras signaling, resulting in increased tumor cell proliferation.
Because of evidence linking CD44 v6 as a marker for HNSCC tumor proliferation and metastasis, a phase I clinical trial was conducted to evaluate anti-CD44 v6 antibody therapy for the treatment of incurable HNSCC, with a 10% response rate reported.23 Administration of anti-CD44 v6 antibody to a CD44 v6 isoform-expressing HNSCC cell line resulted in decreased cell proliferation and increased cisplatin sensitivity.20 Using the same anti-CD44 v6 antibody, immunohistochemical analysis of HNSCC tissue specimens indicated that CD44 v6 isoforms were preferentially expressed in metastatic lymph nodes, and strong expression of CD44 v6 in primary tumors was significantly associated with advanced T status, perineural invasion, and shorter disease-free survival. Although these studies are small, the association of CD44 v6 isoforms with clinically advanced HNSCC and the intriguing results of anti-CD44 v6 therapy in a phase I clinical trial suggest a need for further study of the role of this CD44 variant isoform in HNSCC.
Although all CD44 isoforms share HA binding domains, certain CD44 variant isoforms, such as CD44 v10, exhibit significantly reduced affinity for HA binding. It is thought that the reduction in HA-mediated cell adhesion in tumor cells expressing CD44 v10 may be the earliest event in the onset of tumor migration and invasion. The unique structure of CD44 v10 may also cause constitutive activation of CD44-cytoskeleton interactions that induce tumor cell migration and invasion. CD44 v10-containing isoforms have been reported to promote tumor progression in breast and renal cell carcinoma. Studies have revealed that CD44 v10-transfected breast tumor cells display higher migration/invasion potential, produce higher levels of basic fibroblast growth factor and interleukin-8, and exhibit more potent tumor growth potential than parental control cells. Treatment of a CD44 v10 isoform-expressing HNSCC cell line with anti-CD44 v10 antibody resulted in decreased tumor cell proliferation and increased cisplatin sensitivity. The same anti-CD44 v10 antibody was used in the analysis of HNSCC clinical tissue specimens, demonstrating that CD44 v10 isoforms were preferentially expressed in metastatic lymph nodes. In addition, strong expression of CD44 v10 in primary tumors was significantly associated with distant metastasis, failure of radiotherapy, and shorter disease-free survival. Further studies to establish the interaction of the ligands involved in CD44 v10 signaling in HNSCC are needed to determine its role in HNSCC metastasis and treatment resistance.