scholarly journals Computational Simulation of Exosome Transport in Tumor Microenvironment

2021 ◽  
Vol 8 ◽  
Author(s):  
Roy Koomullil ◽  
Behnam Tehrani ◽  
Kayla Goliwas ◽  
Yong Wang ◽  
Selvarangan Ponnazhagan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Interstitial Fluid ◽  
Computational Simulation ◽  
Fluid Pressure ◽  
Interstitial Flow ◽  
Release Rates ◽  
Oscillatory Force ◽  
And Diffusion

Cellular exosome-mediated crosstalk in tumor microenvironment (TME) is a critical component of anti-tumor immune responses. In addition to particle size, exosome transport and uptake by target cells is influenced by physical and physiological factors, including interstitial fluid pressure, and exosome concentration. These variables differ under both normal and pathological conditions, including cancer. The transport of exosomes in TME is governed by interstitial flow and diffusion. Based on these determinants, mathematical models were adapted to simulate the transport of exosomes in the TME with specified exosome release rates from the tumor cells. In this study, the significance of spatial relationship in exosome-mediated intercellular communication was established by treating their movement in the TME as a continuum using a transport equation, with advection due to interstitial flow and diffusion due to concentration gradients. To quantify the rate of release of exosomes by biomechanical forces acting on the tumor cells, we used a transwell platform with confluent triple negative breast cancer cells 4T1.2 seeded in BioFlex plates exposed to an oscillatory force. Exosome release rates were quantified from 4T1.2 cells seeded at the bottom of the well following the application of either no force or an oscillatory force, and these rates were used to model exosome transport in the transwell. The simulations predicted that a larger number of exosomes reached the membrane of the transwell for 4T1.2 cells exposed to the oscillatory force when compared to controls. Additionally, we simulated the interstitial fluid flow and exosome transport in a 2-dimensional TME with macrophages, T cells, and mixtures of these two populations at two different stages of a tumor growth. Computational simulations were carried out using the commercial computational simulation package, ANSYS/Fluent. The results of this study indicated higher exosome concentrations and larger interstitial fluid pressure at the later stages of the tumor growth. Quantifying the release of exosomes by cancer cells, their transport through the TME, and their concentration in TME will afford a deeper understanding of the mechanisms of these interactions and aid in deriving predictive models for therapeutic intervention.

scholarly journals Interstitial flow promotes macrophage polarization toward an M2 phenotype

2018 ◽  
Vol 29 (16) ◽  
pp. 1927-1940 ◽  
Author(s):  
Ran Li ◽  
Jean Carlos Serrano ◽  
Hao Xing ◽  
Tara A. Lee ◽  
Hesham Azizgolshani ◽  
...  
Keyword(s):  
Fluid Flow ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cell ◽  
Interstitial Fluid ◽  
Macrophage Polarization ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
M2 Polarization ◽  
Tumor Tissues

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

scholarly journals Semaphorin Signaling in Cancer-Associated Inflammation

2019 ◽  
Vol 20 (2) ◽  
pp. 377 ◽  
Author(s):  
Giulia Franzolin ◽  
Luca Tamagnone
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Disease Progression ◽  
Tumor Cells ◽  
Cross Talk ◽  
Immune Cells ◽  
Major Element ◽  
Inflammatory Cells ◽  
Anti Cancer

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

scholarly journals Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1539 ◽  
Author(s):  
Peter Ping Lin
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Mesenchymal Transition ◽  
Tumor Neovascularization ◽  
Hypoxic Tumor

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

Platelet Depletion Reduces Tumor Hypoxia and Metastasis Mediated by Met Signaling Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3321-3321
Author(s):  
Rong Li ◽  
Meiping Ren ◽  
Ni Chen ◽  
Mao Luo ◽  
Jianbo Wu
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Hypoxia ◽  
Hemoglobin Content ◽  
Melanoma Cancer ◽  
And Control ◽  
Platelet Depletion

Abstract Abstract 3321 Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hemorrhagic metastasis. However, the role of platelets in the tumor growth, angiogenesis, and metastasis initiation remains undefined. The B16/F10 melanoma cancer cells model of metastasis and the Lewis lung carcinoma (LLC) spontaneous pulmonary metastasis model were used for this purpose. Using induction of thrombocytopenia, primary tumor growth was monitored and every 3 days anti-GPIbα or rat IgG injections were initiated when tumor reached ∼500mm3and continued until tumor reached to 3 weeks. We showed that platelet depletion had no change in tumor growth but reduced metastasis. Platelet depletion significantly increased pericyte coverage and reduced vascular density compared with control mice. We evaluated the ratio of fluorescence intensities within the plasma and tumor following injection of mice with FITC-dextran. We found that the FITC-dextran was similarly deposited into the tumor tissue in either platelet-depleted or control mice, indicating that tumor vessel perfusion did not differ in either platelet-depleted or control mice. To further gain insight into the molecular mechanisms associated with reduced metastasis resulting from platelet depletion, we assessed hypoxia levels by examining pimonidazole adduct formation in the tumors of platelet-depleted and control mice and found decreased hypoxic levels in the platelet-depleted tumors. In addition, expression of the hypoxia-inducible transcription factor HIF-1α was also significantly reduced in the tumors of platelet-depleted mice. Tumor hypoxia is strongly associated with deposition of hemoglobin. We measured the intratumor hemoglobin content, reflecting the level of erythrocytes extravasation. The hemoglobin content in the tumors of mice with platelet-depletion was significantly higher than that of control mice (172.11 ± 20.2 g/L/g Vs. 110.28 ± 12.4 g/L/g, p<0.05) Based on the known induction effects of hypoxia and cancer invasiveness on the expression and activation of the proinvasive tyrosine kinase receptor Met, we analyzed total protein and tyrosine phosphorylation levels of Met in both platelet-depleted and control mice. Western blotting analysis revealed that platelet-depletion caused a significantly decrease of both total Met and phosph-Met in tumors when compared to tumors from control mice. To evaluate intratumoral growth factor level, microdialysis was performed after 3 weeks and there was a significant decrease of extracellular VEGF and TNF-β in platelet depletion mice compared with control mice. Recent studies demonstrated that abundant platelets were detected in the tumor microenvironment apart from the vasculature. Based on the finding platelets in contact with tumor cells outside the bloodstream, we examined the functional effects of co-implantation of B16/F10 tumor cells with platelets on tumor progression and metastasis. B16/F10 melanoma cancer cells were implanted into back of wild type mice. During a 3-weeks growth, co-implantation of B16/F10 with platelets not only led to promoted tumor volume (3968 ± 296 mm3Vs. 2956 ± 180 mm3, p<0.05) and weight (5.529 ± 0.35 g Vs. 3.943 ± 0.738 g, p<0.05 ) compared with B16/F10 alone implantation, but also led to an increase in metastasis. Furthermore, in vitro co-culture of B16/F10 cancer cells with platelets showed a significant increase in B16/F10 cancer cells invasion compared with B16/F10 cancer cells alone. In conclusion, our findings demonstrate for the first time that platelets play a critical role in the initiation of tumor metastasis. Moreover, our findings suggest that platelets within the primary tumor microenvironment are likely involved in tumor progression and metastasis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Spatial transcriptomics reveals the architecture of the tumor/microenvironment interface

2020 ◽  
Author(s):  
Miranda V. Hunter ◽  
Reuben Moncada ◽  
Joshua M. Weiss ◽  
Itai Yanai ◽  
Richard M. White
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Human Melanoma ◽  
Zebrafish Model ◽  
Interface Cell ◽  
Ets Family

SUMMARYDuring tumor progression, cancer cells come into contact with new cell types in the microenvironment, but it is unclear how tumor cells adapt to new environments. Here, we integrate spatial transcriptomics and scRNA-seq to characterize tumor/microenvironment interactions during the initial steps of invasion. Using a zebrafish model of melanoma, we identify a unique “interface” cell state at the tumor/microenvironment boundary. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. An ETS-driven interface is conserved across ten patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatial transcriptomic approaches in uncovering mechanisms that allow tumors to invade into the microenvironment.

scholarly journals The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanghong Ni ◽  
Xiaoting Zhou ◽  
Jia Yang ◽  
Houhui Shi ◽  
Hongyi Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Tumor Stroma ◽  
Malignant Cells ◽  
Acquired Drug Resistance ◽  
Long Time

Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.

scholarly journals Biologically active Camellia oleifera protein nanoparticles for improving the tumor microenvironment and drug delivery

2020 ◽  
Vol 8 (14) ◽  
pp. 3907-3915
Author(s):  
Xiaoping Qian ◽  
Tinghui Shen ◽  
Xiaoke Zhang ◽  
Chongzhi Wang ◽  
Weibo Cai ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Microenvironment ◽  
Interstitial Fluid ◽  
Therapeutic Response ◽  
Fluid Pressure ◽  
Biologically Active ◽  
Camellia Oleifera ◽  
Solid Stress ◽  
Protein Nanoparticles ◽  
Tumor Interstitial Fluid

Biologically active Camellia oleifera protein nanoparticles can lower tumor interstitial fluid pressure and solid stress, improving the therapeutic response.

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