There is a growing interest in developing microphysiological systems that can be used to model both normal and pathological human organs in vitro. This “organs-on-chips” approach aims to capture key structural and physiological characteristics of the target tissue. Here we describe in vitro vascularized microtumors (VMTs). This “tumor-on-a-chip” platform incorporates human tumor and stromal cells that grow in a 3D extracellular matrix and that depend for survival on nutrient delivery through living, perfused microvessels. Both colorectal and breast cancer cells grow vigorously in the platform and respond to standard-of-care therapies, showing reduced growth and/or regression. Vascular-targeting agents with different mechanisms of action can also be distinguished, and we find that drugs targeting only VEGFRs (Apatinib and Vandetanib) are not effective, whereas drugs that target VEGFRs, PDGFR and Tie2 (Linifanib and Cabozantinib) do regress the vasculature. Tumors in the VMT show strong metabolic heterogeneity when imaged using NADH Fluorescent Lifetime Imaging Microscopy and, compared to their surrounding stroma, many show a higher free/bound NADH ratio consistent with their known preference for aerobic glycolysis. The VMT platform provides a unique model for studying vascularized solid tumors in vitro.
Like the nuclear pore complex, FG repeat–containing P-granule proteins interact to help establish a size-exclusion barrier.
The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma.
Over the past six decades the inflation-adjusted cost to bring a new drug to market has been increasing constantly and doubles every 9 years - now reaching in excess of $2.5 billion. Overall, the likelihood of FDA approval for a drug (any disease indication) that has entered phase I clinical trials is a mere 9.6%, with the approval rate for oncology far below average at only 5.1%. Lack of efficacy or toxicity is often not revealed until the later stages of clinical trials, despite promising preclinical data. This indicates that the current in vitro systems for drug screening need to be improved for better predictability of in vivo outcomes. Microphysiological systems (MPS), or bioengineered 3D microfluidic tissue and organ constructs that mimic physiological and pathological processes in vitro, can be leveraged across preclinical research and clinical trial stages to transform drug development and clinical management for a range of diseases. Here we review the current state-of-the-art in 3D tissue-engineering models developed for cancer research, with a focus on tumor-on-a-chip, or tumor chip, models. From our viewpoint, tumor chip systems can advance innovative medicine to ameliorate the high failure rates in anti-cancer drug development and clinical treatment.
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