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Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma, unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We found similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increased cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects.

Convection-enhanced delivery (CED) is a method used to increase transport of therapeutics in and around brain tumors. CED works through locally applying a pressure differential to drive fluid flow throughout the tumor, such that convective forces dominate over diffusive transport. This allows therapies to bypass the blood brain barrier that would otherwise be too large or solely rely on passive diffusion. However, this also drives fluid flow out through the tumor bulk into surrounding brain parenchyma, which results in increased interstitial fluid (IF) flow, or fluid flow within extracellular spaces in the tissue. IF flow has been associated with altered transport of molecules, extracellular matrix rearrangement, and triggering of cellular motility through a number of mechanisms. Thus, the results of a simple method to increase drug delivery may have unintended consequences on tissue morphology. Clinically, prediction of dispersal of agents via CED is important to catheter design, placement, and implementation to optimize contact of tumor cells with therapeutic agent. Prediction software can aid in this problem, yet we wonder if there is a better way to predict therapeutic distribution based simply on IF flow pathways as determined from pre-intervention imaging. Overall, CED based therapy has seen limited success and we posit that integration and appreciation of altered IF flow may enhance outcomes. Thus, in this manuscript we both review the current state of the art in CED and IF flow mechanistic understanding and relate these two elements to each other in a clinical context.

Glioblastoma (GBM) is the most common and malignant form of brain cancer. Even with aggressive standard of care, GBM almost always recurs because its diffuse, infiltrative nature makes these tumors difficult to treat. The use of biomaterials is one strategy that has been, and is being, employed to study and overcome recurrence. Biomaterials have been used in GBM in two ways: in vitro as mediums in which to model the tumor microenvironment, and in vivo to sustain release of cytotoxic therapeutics. In vitro systems are a useful platform for studying the effects of drugs and tissue-level effectors on tumor cells in a physiologically relevant context. These systems have aided examination of how glioma cells respond to a variety of natural, synthetic, and semi-synthetic biomaterials with varying substrate properties, biochemical factor presentations, and non-malignant parenchymal cell compositions in both 2D and 3D environments. The current in vivo paradigm is completely different, however. Polymeric implants are simply used to line the post-surgical resection cavities and deliver secondary therapies, offering moderate impacts on survival. Instead, perhaps we can use the data generated from in vitro systems to design novel biomaterial-based treatments for GBM akin to a tissue engineering approach. Here we offer our perspective on the topic, summarizing how biomaterials have been used to identify facets of glioma biology in vitro and discussing the elements that show promise for translating these systems in vivo as new therapies for GBM.