Mechanisms that Promote Metastasis in Nasopharyngeal Carcinoma.
Nasopharyngeal carcinoma (NPC) is a cancer of the head and neck, and is particularly
common in Southern China. The non-keratinizing forms of NPC are associated with
infection of the Epstein-Barr virus (EBV). These forms of NPC have been subdivided by
the World Health Organization (WHO) into two classes based on histology: type II (poorly
differentiated), and type III (undifferentiated). ... read moreWe developed a xenograft model of NPC
in immunodeficient mice and found that tumors established with an NPC type III cell line
(C666-1) frequently metastasize to distant tissues, whereas tumors established with an
NPC type II cell line (HONE Akata) do not. This suggests that the distinction that
separates type II and type III may be critical for metastatic progression in NPC. Our
analysis of gene expression data from an Affymetrix study of type II and type III NPC
using the Connectivity Map suggests that the PI3K-Akt-mTOR pathway may be more highly
activated in NPC type III. The array data may also reflect differential sensitivity
between type II and type III to PI3K-Akt-mTOR pathway inhibitors. When mice are treated
with Rapamycin, an mTOR inhibitor, the growth of metastases is significantly reduced.
Taken together, this suggests that the activation of the PI3K-Akt-mTOR pathway may
provide a molecular basis for the distinction between NPC type II and NPC type III, and
may be important for metastatic progression in NPC. It may also provide prognostic and
therapeutic implications for more efficacious treatment specifically targeting
metastatic NPC. Using microarray analysis, we found that the EBV-encoded protein, LMP1,
induces the transcription of the gene that encodes the chemokine CCL5/RANTES in
epithelial cells. The induction of this chemokine, which attracts lymphocytes, including
T cells and macrophages, may provide a possible explanation for the extensive
lymphocytic infiltrate seen in NPC tumors. RANTES has also been reported to play a
causative role in promoting metastasis in models of lung and breast cancer. We therefore
also investigated whether LMP1-induced expression of RANTES drives invasion and
metastasis in NPC. Our data suggest that RANTES enhances the motility of NPC-derived
cell lines and primary cells from NPC biopsies in vitro and may contribute to invasion
and metastasis in our model of NPC in vivo.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Immunology.
Advisor: David Thorley-Lawson.
Committee: Stephen Bunnell, Peter Brodeur, and Philip Tsichlis.
Keywords: Immunology, and Oncology.read less
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