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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2016)

Cancer is one of the deadliest diseases; vast resources have been used to understand its root causes and to elucidate the intricacies of cancer progression in order to develop effective prevention and treatment strategies. Unfortunately, there are a lot of factors in the tumor microenvironment that contribute to cancer development and progression. Consequently, a better understanding of the tumor niche has become an important goal of cancer research. Here we have approached the problem using a combination of in vitro assays and computational modeling. Firstly we studied extracellular matrix (ECM).

Recently, it has been found that the ECM surrounding tumors has significant effects on tumor cell growth and migration. However, there is a shortage of information on how cells respond to normal vs tumor ECM. In order to overcome this problem, we have isolated human tumor ECM (tECM) and compared its chemical and mechanical properties to ECM derived from matched normal tissue (nECM). We next examined the ability of each of these matrices to support the development of new vasculature – a key event in tumor progression. We found that the capillaries that form in the tECM have

characteristics similar to those seen in in vivo tumors. We also found that tumor growth and tumor metabolism is different in these two ECMs, with tumor growth being faster, and tumor cell metabolism more glycolytic, in the tECM. Taken together, these data identify the importance of the ECM in tumor progression and suggest that normalization of ECM morphology and composition could provide a novel strategy to limit tumor growth.

Our second approach used mathematical models to study the interaction of different tumor cell lineages with the vascular niche. We find evidence to support the idea of endothelial cell transdifferentiation into tumor cells. And, the computational simulations of the model indicated that the transdifferentiated glioblastoma cells to have a major contribution in tumor therapy resistance.

    Cover page: Modeling of Human Vascularized Colon Tumors in Three-dimensional Extracted Extracellular Matrices
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2017)

    Objective

    In glioblastoma, the crosstalk between vascular endothelial cells (VECs) and glioma stem cells (GSCs) has been shown to enhance tumor growth. We propose a multiscale mathematical model to study this mechanism, explore tumor growth under various initial and microenvironmental conditions, and investigate the effects of blocking this crosstalk.

    Methods

    We develop a hybrid continuum-discrete model of highly organized vascularized tumors. VEC-GSC crosstalk is modeled via vascular endothelial growth factor (VEGF) production by tumor cells and by secretion of soluble factors by VECs that promote GSC self-renewal and proliferation.

    Results

    VEC-GSC crosstalk increases both tumor size and GSC fraction by enhancing GSC activity and neovascular development. VEGF promotes vessel formation, and larger VEGF sources typically increase vessel numbers, which enhances tumor growth and stabilizes the tumor shape. Increasing the initial GSC fraction has a similar effect. Partially disrupting the crosstalk by blocking VEC secretion of GSC promoters reduces tumor size but does not increase invasiveness, which is in contrast to antiangiogenic therapies, which reduce tumor size but may significantly increase tumor invasiveness.

    Significance

    Multiscale modeling supports the targeting of VEC-GSC crosstalk as a promising approach for cancer therapy.
      Cover page: Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression Without Increasing Invasiveness
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2017)
      e13535 Background: Glioblastoma (GBM), the most aggressive brain tumor in human patients, is highly heterogeneous and intensively vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and by promoting resistance to therapy. Recently, crosstalk between GSCs and vascular endothelial cells that line capillaries has been shown to considerably promote GSC self-renewal and tumor progression. GSCs have been shown to also transdifferentiate into bona-fide vascular endothelial cells (GEC). GECs inherit mutations present in GSCs and are resistant to traditional anti-angiogenic therapies. Methods: We develop a multispecies mathematical model to investigate the 3D spatiotemporal dynamics of vascularized GBM progression and response to cancer therapies. Results: The model predicts GSCs drive invasive fingering and that GECs spontaneously form a network within the hypoxic core, consistent with published experimental findings. We demonstrate that standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies reduce GBM tumor sizes but increase invasiveness. Anti-GEC treatments block the GEC support of GSCs and reduce tumor sizes but can lead to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness and sizes, but are ultimately limited in reducing tumor sizes because GECs can maintain GSCs. Anti-GEC therapies are required to remove the tumor completely. Conclusions: Our results suggest that a combinatorial regimen targeting the vasculature, GSCs and GECs, using drugs already approved by the FDA, can reduce both tumor sizes and invasiveness and could lead to tumor eradication without recurrence when the treatment is stopped.
        Cover page: 3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2018)
          Cover page: Multiscale modeling of glioblastoma.Creative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2014)
          The Snail family of zinc-finger transcription factors are evolutionarily conserved proteins that control processes requiring cell movement. Specifically, they regulate epithelial-to-mesenchymal transitions (EMT) where an epithelial cell severs intercellular junctions, degrades basement membrane and becomes a migratory, mesenchymal-like cell. Interestingly, Slug expression has been observed in angiogenic endothelial cells (EC) in vivo, suggesting that angiogenic sprouting may share common attributes with EMT. Here, we demonstrate that sprouting EC in vitro express both Slug and Snail, and that siRNA-mediated knockdown of either inhibits sprouting and migration in multiple in vitro angiogenesis assays. We find that expression of MT1-MMP, but not of VE-Cadherin, is regulated by Slug and that loss of sprouting as a consequence of reduced Slug expression can be reversed by lentiviral-mediated re-expression of MT1-MMP. Activity of MMP2 and MMP9 are also affected by Slug expression, likely through MT1-MMP. Importantly, we find enhanced expression of Slug in EC in human colorectal cancer samples compared with normal colon tissue, suggesting a role for Slug in pathological angiogenesis. In summary, these data implicate Slug as an important regulator of sprouting angiogenesis, particularly in pathological settings.
            Cover page: Angiogenic sprouting is regulated by endothelial cell expression of SlugCreative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2017)
            Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. Cancer Res; 77(15); 4171-84. ©2017 AACR.
              Cover page: 3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2016)
              Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies. Extracellular matrix (ECM) influences cellular behavior and maturation, as does the geometry of the environment-two-dimensional (2D) versus three-dimensional (3D). We therefore tested the hypothesis that native cardiac ECM and 3D cultures might enhance the maturation of iPSC-derived CMs in vitro. We demonstrate that maturation of iPSC-derived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECM promoted increased expression of calcium-handling genes, Junctin, CaV1.2, NCX1, HCN4, SERCA2a, Triadin, and CASQ2. Consistent with this, we find that iPSC-derived CMs in 3D adult cardiac ECM show increased calcium signaling (amplitude) and kinetics (maximum upstroke and downstroke) compared with cells in 2D. Cells in 3D culture were also more responsive to caffeine, likely reflecting an increased availability of calcium in the sarcoplasmic reticulum. Taken together, these studies provide novel strategies for maturing iPSC-derived CMs that may have applications in drug screening and transplantation therapies to treat heart disease.
                Cover page: Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived CardiomyocytesCreative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2017)
                Extracellular matrix (ECM) is an essential and dynamic component of all tissues and directly affects cellular behavior by providing both mechanical and biochemical signaling cues. Changes in ECM can alter tissue homeostasis, potentially leading to promotion of cellular transformation and the generation of tumors. Therefore, understanding ECM compositional changes during cancer progression is vital to the development of targeted treatments. Previous efforts to reproduce the native 3D cellular microenvironment have utilized protein gels and scaffolds that incompletely recapitulate the complexity of native tissues. Here, we address this problem by extracting and comparing ECM from normal human colon and colon tumor that had metastasized to liver. We found differences in protein composition and stiffness, and observed significant differences in vascular network formation and tumor growth in each of the reconstituted matrices, both in vitro and in vivo. We studied free/bound ratios of NADH in the tumor and endothelial cells using Fluorescence Lifetime Imaging Microscopy as a surrogate for the metabolic state of the cells. We observed that cells seeded in tumor ECM had higher relative levels of free NADH, consistent with a higher glycolytic rate, than those seeded in normal ECM. These results demonstrate that the ECM plays an important role in the growth of cancer cells and their associated vasculature.
                  Cover page: Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growthCreative Commons 'BY' version 4.0 license
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