Abstract:
:High microvascular density (MVD) in the primary tumor has been shown to be associated with increased incidence of lymph node metastases and poor clinical outcome. Other investigations have revealed that a large fraction of hypoxic tissue in the primary tumor is associated with metastatic disease and impaired survival. These data are apparently incompatible because tumor hypoxia is primarily a consequence of poor oxygen supply caused by an inadequate vasculature with increased intervessel distances. Here, we provide an explanation of these observations. Human melanoma xenografts were used as preclinical cancer models. Tumors that metastasized to lymph nodes showed higher interstitial fluid pressure (IFP) than those that did not metastasize, and compared with tumors with low IFP, tumors with high IFP showed large hypoxic fractions centrally, high MVD in the periphery, high peritumoral density of lymphatics, and elevated expression of vascular endothelial growth factor A (VEGF-A) and VEGF-C. Significant correlations were found between peripheral MVD and central hypoxia, and lymph node metastasis was associated with high values of both parameters. These findings suggest that the outcome of cancer may be associated with both high MVD and extensive hypoxia in the primary tumor. We propose that proangiogenic factors are upregulated in the tumor center and that the outward interstitial fluid flow caused by the elevated IFP transports these factors to the tumor surface where they evoke hemangiogenesis and lymphangiogenesis, and consequently, that the IFP serves as a link between tumor hypoxia, peripheral tumor hemangiogenesis, peritumoral lymphangiogenesis, and lymph node metastasis.
journal_name
Neoplasiajournal_title
Neoplasia (New York, N.Y.)authors
Rofstad EK,Galappathi K,Mathiesen BSdoi
10.1016/j.neo.2014.07.003subject
Has Abstractpub_date
2014-07-01 00:00:00pages
586-94issue
7eissn
1522-8002issn
1476-5586pii
S1476-5586(14)00089-Xjournal_volume
16pub_type
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