Abstract

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Uncovering mechanisms underlying metastasis is the final frontier in cancer biology. Metastasis is a complex process with many discrete stages. While there has been much research on the seed (metastatic tumor cells) and the soil (colonized host tissue) hypothesis, limited knowledge exists on the interaction between metastatic cells and vascular endothelial cells, prerequisite for the development of metastatic disease.

Here we describe nanoscale tubular structures, or nanoChannels (nCs), which mediate early intercellular communication between tumor epithelial cells and the endothelium in vitro and in vivo. These structures were examined in a 3D in vitro co-culture model system capturing molecular and physical interactions between metastatic cells and the endothelium. Unlike classical modes of cell-cell communication (i.e. paracrine, endocrine, and autocrine signaling), nCs allow for both rapid and directed transfer of intracellular contents from metastatic breast cancer cells to the endothelium. The ability to form nanoChannels correlates with metastatic potential of the tumor cells and enables direct tracking of both synthetic materials (chemicals and nanoparticles) and bioorganic macromolecules (proteins and miRNAs). As one specific example, we show that miR-132, which is implicated in pathological angiogenesis, can translocate from tumor cells to the endothelial cells through nCs, resulting in decreased p120RasGAP and activation of AKT in the recipient endothelial cells. Furthermore, nC-mediated communication resulted in upregulation of pathological angiogenesis markers, such as CD137 (26x, p<0.001) and CD276 (2x, p<0.001). The increase in these pathological angiogenesis markers could be reduced by pharmacological inhibition of nC formation. Combination of 500pM Docetaxel with 30nM Latrunculin A or 50nM Cytoclasin D resulted in a 3x (p<0.01) disruption of TNT structures, reducing TNT-mediated communication by 42% (p<0.0001) and 56.6% (p<0.0001), respectively.

In summary, we describe a novel form of heterotypic intercellular communication between cancer cells and the host endothelium, where tumor cells can physically hijack and transform normal endothelial cells to a pathological angiogenesis phenotype. We define this process as metastatic parasitism. NanoChannel-mediated transfer of microRNAs may emerge as a new signaling mechanism in metastasis, which may function to prime the endothelium to facilitate transmigration of tumor cells and/or recruitment of vasculature to growing metastases. Elucidation of microRNAs transported through the nanoChannels presents a powerful opportunity to explain mechanisms underlying pathological angiogenesis and for the development of metastasis-specific therapeutics. Targeting the formation of these nCs and the resulting metastatic parasitism may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.

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Yamicia D. Connor, Sarah Tekleab, Amjad Husain, Cherelle Walls, Bruce Zetter, Harold Dvorak, Shiladitya Sengupta. NanoChannel-mediated communication between tumor cells and endothelium mediates metastatic parasitism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3600. doi:10.1158/1538-7445.AM2014-3600

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