380212 Tumor Vascular Status Regulates Molecular Dissemination into Regional and Systemic Tissues

Tuesday, November 18, 2014: 9:42 AM
201 (Hilton Atlanta)
Nathan A. Rohner and Susan N. Thomas, George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA

Tumors secrete biomolecules (proteins, exosomes) of a broad range of physiochemical properties (chain-like biopolymers, membrane-enclosed particulates) and sizes (1-5 nanometer (nm) in hydrodynamic radius, 30-100 nm in diameter) that are hypothesized to precondition the metastatic niche. However, it is not well understood by what route these biomolecules escape from the primary tumor to accumulate within their site of action. Since normal blood capillaries are permeable only to low molecular weight (MW) solutes (<5 nm in diameter), lymphatic drainage supports the clearance of intermediate MW solutes (>40kDa or >5nm diameter but <100 nm) from the intercapillary tissue space, and cell-mediated trafficking clears large particulates (>100 nm), molecular size characteristics are hypothesized to crucially influence their clearance profile and capacity to disseminate systemically. However, though the tumor vascular plexus is well described to be irregular and highly permeable, how it influences the extent and rate of molecular clearance as well as blood versus lymphatic partitioning of low versus high MW tumor-derived molecules remains ill-defined. To address this issue, the contribution of the developing tumor vasculature on molecular clearance and dissemination patterns was investigated by comparing the transport patterns of fluorescently labeled molecules from healthy versus malignant tissues that display well-documented changes in their complex neo-vascular plexus with tumor progression. We found that progression of B16F10 melanoma in C57Bl6 animals for seven days or more resulted in dramatically reduced (>75%) lymphatic transport relative to that from normal (naïve) skin tissue, which resulted in reduced sentinel (tumor-draining) lymph node molecular accumulation. Advanced tumors also demonstrated disrupted permeability profiles that resulted in altered systemic accumulation of injected molecular beacons relative to healthy tissues. Experimental results from these temporal biodistribution studies and pharmacodynamic modeling will be discussed in depth. In summary, this work suggests that altered vascular profiles within malignant skin results in molecular clearance and dissemination patterns that are absent from healthy animals and may reveal the utility of angioplastic therapeutics for mitigation of the role of molecular transport in metastasis.

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