scholarly journals Matrix density drives 3D organotypic lymphatic vessel activation in a microfluidic model of the breast tumor microenvironment

Lab on a Chip ◽  
2020 ◽  
Vol 20 (9) ◽  
pp. 1586-1600 ◽  
Author(s):  
Karina M. Lugo-Cintrón ◽  
José M. Ayuso ◽  
Bridget R. White ◽  
Paul M. Harari ◽  
Suzanne M. Ponik ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Lymphatic Vessel ◽  
Therapeutic Targets ◽  
Matrix Density

Lymphatic organotypic in vitro model allows the examination of components of the tumor microenvironment (e.g., ECM density, cancer cells) in lymphatic vessel biology in the context of cancer, providing insights into potential therapeutic targets.

Estrogen receptor β represses breast tumor growth and angiogenesis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10101-10101
Author(s):  
J. Hartman ◽  
K. Lindberg ◽  
J. Inzunza ◽  
J. Wan ◽  
A. Ström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Angiogenic Effect

10101 Background: Estrogens are well known stimulators of breast cancer cell growth in vitro as well as in vivo. Two different estrogen receptors exist, namely estrogen receptor (ER) α and β. ERα mediates the proliferative effect of estrogen in breast cancer cells and we have earlier shown that ERβ inhibits cell-cycle progression in vitro. Estrogens are well known stimulators of in vivo breast cancer cell growth as well as angiogenesis, and the effect is mediated through ERα. The function of ERβ in this context is not well understood. Methods: We have used ERα-positive T47D breast cancer cells stably transfected with a Tet/Off regulated ERβ expression vector system. The ERβ-inducible tumor cells are studied in vitro as well as in vivo. Results: By transplanting ERβ-inducible breast cancer cells into SCID-mice, we show that ERβ inhibits tumor growth and reduces the volume of established tumors. Furthermore, we show by immunohistochemistry, that the number of blood microvessels in the tumor periphery is decreased by ERβ expression, counteracting the well-known pro-angiogenic effect of ERα. By Western blot analysis on tumor extracts, we show that the concentration of the important pro-angiogenic growth factors VEGF and bFGF, normally expressed by breast tumor cells, is decreased in the ERβ-expressing tumors compared to the normal tumors. To exclude that the observed anti-angiogenic effect is just a result of reduced tumor growth, we incubated Tet/Off regulated ERβ expressing cells in vitro, during non-hypoxic conditions. We found that the expression of ERβ leads to decreased expression of VEGF and PDGFβ at the mRNA and protein-levels. In transient transfection assays, we found estrogen-ERα mediated up regulation of VEGF, PDGFβ and bFGF-promoter activities in T47D cells, and these activities were all suppressed following co-transfection with an ERβ-expression vector. Conclusions: We conclude that ERβ inhibits growth factor expression at transcriptional level in breast cancer cells; taken together, our data indicates that ERβ inhibits growth and angiogenesis of tumors formed by T47D breast cancer cells. This makes ERβ an interesting therapeutic target in breast cancer and perhaps treatment with the newly designed ERβ-selective ligands might work as a new anti-proliferative and anti-angiogenic therapy. No significant financial relationships to disclose.

scholarly journals PEPT1 is essential for the growth of pancreatic cancer cells: A viable drug target

2021 ◽  
Author(s):  
Bradley Schniers ◽  
Devaraja Rajasekaran ◽  
Ksenija Korac ◽  
Tyler Sniegowski ◽  
Vadivel Ganapathy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cell Lines ◽  
Intracellular Localization ◽  
Peptide Transporter ◽  
Pdac Cell ◽  
Functional Link ◽  
Pancreatic Cancer Cells

PEPT1 is a proton-coupled peptide transporter that is upregulated in PDAC cell lines and PDXs, with little expression in normal pancreas. However, the relevance of this upregulation to cancer progression and the mechanism of upregulation have not been investigated. Herein, we show that PEPT1 is not just upregulated in a large panel of PDAC cell lines and PDXs but is also functional and transport-competent. PEPT2, another proton-coupled peptide transporter, is also overexpressed in PDAC cell lines and PDXs, but is not functional due to its intracellular localization. Using glibenclamide as a pharmacological inhibitor of PEPT1, we demonstrate in cell lines in vitro and mouse xenografts in vivothat inh­­ibition of PEPT1 reduces the proliferation of the cancer cells. These findings are supported by genetic knockdown of PEPT1 with shRNA, wherein the absence of the transporter significantly attenuates the growth of cancer cells, both in vitro and in vivo, suggesting that PEPT1 is critical for the survival of cancer cells. We also establish that the tumor-derived lactic acid (Warburg effect) in the tumor microenvironment supports the transport function of PEPT1 in the maintenance of amino acid nutrition in cancer cells by inducing MMPs and DPPIV to generate peptide substrates for PEPT1 and by generating a H+ gradient across the plasma membrane to energize PEPT1. Taken collectively, these studies demonstrate a functional link between PEPT1 and extracellular protein breakdown in the tumor microenvironment as a key determinant of pancreatic cancer growth, thus identifying PEPT1 as a potential therapeutic target for PDAC.

scholarly journals Tumor-Intrinsic Response to IFNγ Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

2019 ◽  
Author(s):  
Bonnie L. Bullock ◽  
Abigail K. Kimball ◽  
Joanna M. Poczobutt ◽  
Howard Y. Li ◽  
Jeff W. Kwak ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Rna Seq ◽  
Lung Cancer Cell ◽  
Immunocompetent Mouse ◽  
Lung Cancer Patients ◽  
T Cell Infiltration ◽  
Basal Expression

AbstractTargeting PD-1/ PD-L1 is only effective in ~20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated while LLC tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA-Seq analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was absent in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of Socs1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped TME, characterized by enhanced T cell infiltration and enrichment of PD-L1 high myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce of cascade of changes associated with increased therapeutic vulnerability.SummaryMechanisms regulating response to anti-PD-1 therapy in lung cancer are not well defined. This study, using orthotopic immunocompetent mouse models of lung cancer, demonstrates that intrinsic sensitivity of cancer cells to IFNγ determines anti-PD-1 responsiveness through alterations in the tumor microenvironment.

scholarly journals Three-Dimensional In Vitro Lymphangiogenesis Model in Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Youngkyu Cho ◽  
Kyuhwan Na ◽  
Yesl Jun ◽  
Jihee Won ◽  
Ji Hun Yang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Metastasis ◽  
Lymphatic Vessel ◽  
Disease Model ◽  
Three Dimensional ◽  
Lymphatic Vessels ◽  
Dimensional Structure ◽  
Biomechanical Stress

Lymphangiogenesis is a stage of new lymphatic vessel formation in development and pathology, such as inflammation and tumor metastasis. Physiologically relevant models of lymphatic vessels have been in demand because studies on lymphatic vessels are required for understanding the mechanism of tumor metastasis. In this study, a new three-dimensional lymphangiogenesis model in a tumor microenvironment is proposed, using a newly designed macrofluidic platform. It is verified that controllable biochemical and biomechanical cues, which contribute to lymphangiogenesis, can be applied in this platform. In particular, this model demonstrates that a reconstituted lymphatic vessel has an in vivo–like lymphatic vessel in both physical and biochemical aspects. Since biomechanical stress with a biochemical factor influences robust directional lymphatic sprouting, whether our model closely approximates in vivo, the initial lymphatics in terms of the morphological and genetic signatures is investigated. Furthermore, attempting an incorporation with a tumor spheroid, this study successfully develops a complex tumor microenvironment model for use in lymphangiogenesis and reveals the microenvironment factors that contribute to tumor metastasis. As a first attempt at a coculture model, this reconstituted model is a novel system with a fully three-dimensional structure and can be a powerful tool for pathological drug screening or disease model.

scholarly journals Studying Adipose Tissue in the Breast Tumor Microenvironment In Vitro: Progress and Opportunities

2020 ◽  
Vol 17 (6) ◽  
pp. 773-785 ◽  
Author(s):  
David Mertz ◽  
Jason Sentosa ◽  
Gary Luker ◽  
Shuichi Takayama
Keyword(s):  
Adipose Tissue ◽  
Tumor Microenvironment ◽  
Breast Tumor

scholarly journals An in vitro tumorigenesis model based on live-cell-generated oxygen and nutrient gradients

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anne C. Gilmore ◽  
Sarah J. Flaherty ◽  
Veena Somasundaram ◽  
David A. Scheiblin ◽  
Stephen J. Lockett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Live Cell ◽  
Model Systems ◽  
Current Cell ◽  
Nutrient Gradients ◽  
Spatially Varying

AbstractThe tumor microenvironment (TME) is multi-cellular, spatially heterogenous, and contains cell-generated gradients of soluble molecules. Current cell-based model systems lack this complexity or are difficult to interrogate microscopically. We present a 2D live-cell chamber that approximates the TME and demonstrate that breast cancer cells and macrophages generate hypoxic and nutrient gradients, self-organize, and have spatially varying phenotypes along the gradients, leading to new insights into tumorigenesis.

scholarly journals The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1931 ◽  
Author(s):  
Roberta Armignacco ◽  
Giulia Cantini ◽  
Giada Poli ◽  
Daniele Guasti ◽  
Gabriella Nesi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Adrenocortical Carcinoma ◽  
Cancer Cell Line ◽  
Cell Types ◽  
Adrenocortical Cancer ◽  
Solid Malignancies ◽  
H295r Cells

Metabolic interplay between the tumor microenvironment and cancer cells is a potential target for novel anti-cancer approaches. Among stromal components, adipocytes and adipose precursors have been shown to actively participate in tumor progression in several solid malignancies. In adrenocortical carcinoma (ACC), a rare endocrine neoplasia with a poor prognosis, cancer cells often infiltrate the fat mass surrounding the adrenal organ, enabling possible crosstalk with the adipose cells. Here, by using an in vitro co-culture system, we show that the interaction between adipose-derived stem cells (ASCs) and the adrenocortical cancer cell line H295R leads to metabolic and functional reprogramming of both cell types: cancer cells limit differentiation and increase proliferation of ASCs, which in turn support tumor growth and invasion. This effect associates with a shift from the paracrine cancer-promoting IGF2 axis towards an ASC-associated leptin axis, along with a shift in the SDF-1 axis towards CXCR7 expression in H295R cells. In conclusion, our findings suggest that adipose precursors, as pivotal components of the ACC microenvironment, promote cancer cell reprogramming and invasion, opening new perspectives for the development of more effective therapeutic approaches.

scholarly journals N-(3-oxododecanoyl)-L-homoserine lactone interactions in the breast tumor microenvironment: Implications for breast cancer viability and proliferation in vitro

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0180372 ◽  
Author(s):  
Brittany N. Balhouse ◽  
Logan Patterson ◽  
Eva M. Schmelz ◽  
Daniel J. Slade ◽  
Scott S. Verbridge
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Breast Tumor ◽  
Homoserine Lactone ◽  
Proliferation In Vitro

scholarly journals 772 A potent and off-the-shelf oNK cell therapy product targets HER2+ cancer cells and resists suppressive tumor microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A821-A821
Author(s):  
Hao-Kang Li ◽  
Ching-Wen Hsiao ◽  
Sen-Han Yang ◽  
Hsiu-Ping Yang ◽  
Tai-Sheng Wu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Membrane Proteins ◽  
Cell Therapy ◽  
Nk Cells ◽  
Cancer Cells ◽  
Cell Line ◽  
Nk Cell ◽  
Binding Specificity ◽  
Cell Therapy Product

BackgroundAutologous or allogeneic natural killer (NK) cells possess efficient cytotoxicity against tumor cells without severe side effects such as CRS or graft-versus-host disease (GvHD). In addition to chimeric antigen receptor (CAR) strategy, antibody-cell conjugates (ACC) platform provides more efficient way to arm NK cells with binding specificity and enhanced potency against target cells. In this work, we develop a NK cell therapy product ACE1702, a novel NK cell line oNK conjugated with trastuzumab, and assess its potency against HER2+ solid tumors.Methods oNK cells were covalently conjugated with monoclonal antibody Trastuzumab after sublethal irradiation by our patented antibody-cell conjugates (ACC) platform to become our cryopreserved final product ACE1702 compliant with current good manufacturing practice (cGMP). Function of ACE1702 was validated by real-time xCELLigence analyzer and MTT assay in vitro. Efficacy of intraperitoneally (ip.) delivered ACE1702 was evaluated in tumor-bearing female immune compromised NSG mice. Characterization of ACE1702 was analyzed by flow cytometry.ResultsWe demonstrated that the trastuzumab-armed oNK cells, ACE1702, exerted human epidermal growth factor 2 (HER2) binding specificity and enhanced cytotoxicity against various types of cancer cells with different grade of HER2 expressions compared to control oNK cells in vitro. In vivo results in human ovarian cancer cell line SK-OV-3-bearing xenograft mouse model further supported the in vitro observations. Of note, ACE1702 also displayed a better cytotoxicity against HER2+ cancer cells than trastuzumab and its derived antibody-drug conjugate. ACE1702 also remained cytotoxicity against cancer cells in the suppressive tumor microenvironment. Characterization revealed a preferential expression of NK activation receptors, and conjugation of trastuzumab with cell membrane proteins responsible for NK activity capacitated ACE1702 with enhanced cytotoxicity. These results underscore the potency of ACE1702 in eradication of cancer cells.ConclusionsHere we introduced a novel trastuzumab-modified oNK cell product with enhanced specificity against myriad types of HER2+ cancers. Selective conjugation of trastuzumab with membrane proteins contributing to NK activation conferred ACE1702 with enhanced cytotoxicity even in the suppressive tumor microenvironment.AcknowledgementsNoneTrial RegistrationNoneEthics ApprovalThe animal study was conducted according to protocols approved by the Institutional Animal Care and Use Committee of Muragenics.ConsentNone

scholarly journals Investigation of Nano-Bio Interactions within a Pancreatic Tumor Microenvironment for the Advancement of Nanomedicine in Cancer Treatment

2021 ◽  
Vol 28 (3) ◽  
pp. 1962-1979
Author(s):  
Abdulaziz Alhussan ◽  
Kyle Bromma ◽  
Ece Pinar Demirci Bozdoğan ◽  
Andrew Metcalfe ◽  
Joanna Karasinska ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Pancreatic Tumor ◽  
Cell Types ◽  
Time Period ◽  
Physical And Chemical ◽  
Pancreatic Origin

Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of only 10%. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy and chemotherapy. However, the interaction of nanoparticles (NPs) with cancer cells and with other major cell types within the pancreatic tumor microenvironment (TME) is yet to be understood. Therefore, our goal is to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined in this study due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles were used as the model NP system due to their biocompatibility and physical and chemical proprieties, and their dynamics were studied both quantitatively and qualitatively in vitro and in vivo. The in vitro studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. Most importantly, they all managed to retain 70–80% of NPs over a 24-h time period. Uptake and retention of NPs within an in vivo environment was also consistent with in vitro results. This study shows the paradigm-changing potential of NPs to combat the disease.

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