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Dvorak, Harold

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Dvorak

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Harold

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Dvorak, Harold

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2012 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.88729a38-da75-47c6-8e35-68f0ce2c7749

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    Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype
    (2015) Connor, Yamicia; Tekleab, Sarah; Nandakumar, Shyama; Walls, Cherelle; Tekleab, Yonatan; Husain, Amjad; Gadish, Or; Sabbisetti, Venkata; Kaushik, Shelly; Sehrawat, Seema; Kulkarni, Ashish; Dvorak, Harold; Zetter, Bruce; Edelman, Elazer; Sengupta, Shiladitya
    Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of ‘metastatic hijack’: cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.
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    Heterogeneity of the Tumor Vasculature: The Need for New Tumor Blood Vessel Type-Specific Targets
    (Springer Netherlands, 2012) Nagy, Janice A.; Dvorak, Harold
    Therapies directed against VEGF-A and its receptors are effective in treating many mouse tumors but have been less so in treating human cancer patients. To elucidate the reasons that might be responsible for this difference in response, we investigated the nature of the blood vessels that appear in human and mouse cancers and the tumor “surrogate” blood vessels that develop in immunodeficient mice in response to an adenovirus expressing \(VEGF-A^{164}\). Both tumor and tumor surrogate blood vessels are heterogeneous and form by two distinct processes, angiogenesis and arterio-venogenesis. The first new angiogenic blood vessels to form are mother vessels (MV); MV arise from preexisting venules and capillaries and evolve over time into glomeruloid microvascular proliferations (GMP) and subsequently into capillaries and vascular malformations (VM). Arterio-venogenesis results from the remodeling and enlargement of preexisting arteries and veins, leading to the formation of feeder arteries (FA) and draining veins (DV) that supply and drain angiogenic vessels. Of these different blood vessel types, only the two that form first, MV and GMP, were highly responsive to anti-VEGF therapy, whereas “late”-formed capillaries, VM, FA and DV were relatively unresponsive. This finding may explain, at least in part, the relatively poor response of human cancers to anti-VEGF/VEGFR therapies, because human cancers, present for months or years prior to discovery, are expected to contain a large proportion of late-formed blood vessels. The future of anti-vascular cancer therapy may depend on finding new targets on “late” vessels, apart from those associated with the VEGF/VEGFR axis.