Molecular Mechanism of Lymph Node Metastasis in Breast Cancer
Final rept. 1 Sep 2008-31 Aug 2010
NEBRASKA UNIV MEDICAL CENTER OMAHA
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Many challenges exist in the current management of metastatic breast cancer as there are fewer recognized therapeutic strategies. Therefore, a better understanding of the molecular events in the metastatic process is critical. Several reports have described correlation of hyaluronam HA with initiation and progression of various types of epithelial cancers. The HA synthase HAS isoforms encode the enzymes that produce and deposit HA while the hyaluronidase HYAL genes code for enzymes that degrade HA and their expression is dysregulated in various tumors as a result of transcriptional and epigenetic changes that accompany progression. In this report, demonstrate that Has2Has3 knock-down and LYVE1 overexpression modulated mammary tumor growth and spontaneous metastasis. Moreover, expression of CCR7 had no effect on primary tumor growth, but affects lymph node metastasis and CCL21-induced chemotaxis. Hyaluronan did not affect CCL21 expression in mammary tumor cells. Lymph endothelial cells constitutively express CCL21, which is not affected following treatment with hyaluronan. Together, these data suggest an important role of HAS2, LYVE1 and CCR7 in a complex interaction between tumor cells and lymph endothelial cells during mammary tumor growth, angiogenesis, invasion, and lymph node and distant metastasis.
- Medicine and Medical Research