Introduction Tumour cell metastasis to lymph nodes is a frequent clinical feature of colorectal cancer and often heralds a poor clinical outcome. Although tumoural lymphangiogenesis is assumed to contribute to this process there is little evidence to support any notion of a simple correlation between lymphatic vessel density and colorectal cancer metastasis. Growing evidence of complex functional and biochemical interactions between tumour cells and the tumour microvasculature imply that tumoural lymphatics may possess specific phenotypes capable of facilitating tumour cell entry and spread to draining lymph nodes.
Methods We compared the RNA profile of primary lymphatic endothelial cells isolated from tumour and normal tissue using the lymph node metastasising murine T-241/VEGF-C fibrosarcoma model. These results were validated immunohistochemically in several human cancers, including colorectal cancer. The prognostic significance of two differentially expressed genes on tumoural lymphatics was assessed by immunofluorescence microscopy on a panel of mixed stage colorectal cancer tissues.
Results We reveal significant differences in the expression of some 792 genes between normal and tumour lymphatic endothelial cells (ie, >2× fold up/downregulation). These include genes that code for a variety of proteins including components of endothelial junctions, subendothelial matrix, and vessel growth/patterning. We investigated two of these differentially expressed genes in colorectal cancer; Endothelial Specific Adhesion Molecule (ESAM), a tight junction regulatory protein, and Endoglin (CD105), the transforming growth factor-β coreceptor. We reveal that ESAM and Endoglin are significantly upregulated on the lymphatics of colorectal cancer relative to normal tissue, with quantitative analysis of lymphatic vessel staining revealing a dramatic association between the incidence of ESAM positive tumour vessels and the presence of lymph node metastasis.
Conclusion These findings reveal a remarkable degree of phenotypic plasticity in cancer lymphatics and provide new insight into the processes of lymphatic invasion and lymph node metastasis. The detailed characterisation of such qualitative changes may allow the development of better prognostic indicators in colorectal cancer and enlighten the search for improved anti-metastatic therapies.
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