Peter Polverini
University of Michigan, School of Dentistry, Faculty Member
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Scatter factor (SF), a fibroblast-derived cytokine characterized by its ability to convert non-motile epithelial cells to a motile fibroblast-like phenotype, is identical to hepatocyte growth factor (HGF), a broad-spectrum mitogen. SF is... more
Scatter factor (SF), a fibroblast-derived cytokine characterized by its ability to convert non-motile epithelial cells to a motile fibroblast-like phenotype, is identical to hepatocyte growth factor (HGF), a broad-spectrum mitogen. SF is a heterodimeric glycoprotein that is homologous to plasminogen and other blood coagulation proteases but lacks proteolytic activity. Its receptor is the c-met proto-oncogene product, a growth factor receptor-like transmembrane tyrosine kinase. This unique cytokine is also synthesized and secreted by vascular smooth muscle cells and acts on endothelial cells to stimulate migration, protease production, invasion, proliferation, and differentiation into capillary-like tubes in vitro. SF-containing implants in mouse subcutaneous tissue and rat cornea induce directed ingrowth of new blood vessels from surrounding tissue, with maximal angiogenic responses at doses of 100-200 ng of SF. Immunoreactive SF is expressed at sites of neovascularization within human psoriatic plaques. These findings suggest that SF may play a significant role in the formation and repair of blood vessels under physiologic and pathologic conditions.
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Several recently identified proteins such as Bcl-2 and Bcl-x have been found to regulate programmed cell death (i.e., apoptosis). In this report, we examined the levels of expression of proteins that can either prevent apoptosis (i.e.,... more
Several recently identified proteins such as Bcl-2 and Bcl-x have been found to regulate programmed cell death (i.e., apoptosis). In this report, we examined the levels of expression of proteins that can either prevent apoptosis (i.e., Bcl-2 or the long form of Bcl-x, designated Bcl-x1) or promote apoptosis (i.e., Bax or the short form of Bcl-x, designated Bcl-xs) in proliferating benign and malignant endothelial cells (ECs). In normal skin with quiescent ECs, no detection by immunohistochemical staining was observed for Bcl-xL, Bcl-xs, or Bcl-2. However, in diseased skin samples that feature a prominent angiogenic response such as in psoriasis or pyogenic granulomas, the proliferating ECs markedly overexpressed Bcl-xL, with little to no Bcl-2. In an acquired-immune-deficiency-syndrome-related neoplasm, Kaposi's sarcoma, the spindle-shaped tumor cells also overexpressed Bcl-xL compared with Bcl-2. These in vivo studies were extended in vitro using cultured ECs and Kaposi's sarcoma tumor cells that were examined by flow cytometry and immunoblot analysis. Both cultured ECs and Kaposi's sarcoma tumor cells express significantly higher levels of Bcl-xL than Bcl-2. Such overexpression of cell survival gene products may contribute to prolonging the longevity of EC-derived cells in several different benign and neoplastic skin disorders that are characterized by a prominent angiogenic tissue response.
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Angiogenesis is an essential component of normal wound repair, yet the primary mediators of wound angiogenesis have not been well described. The current study characterizes the contribution of vascular endothelial cell growth factor... more
Angiogenesis is an essential component of normal wound repair, yet the primary mediators of wound angiogenesis have not been well described. The current study characterizes the contribution of vascular endothelial cell growth factor (VEGF) to the angiogenic environment of human surgical wounds. Surgical wound fluid samples (n = 70) were collected daily for up to 7 postoperative days (POD) from 14 patients undergoing mastectomy or neck dissection. VEGF levels in surgical wound fluid were lowest on POD 0, approximating values of serum, but increased steadily through POD 7. An opposite pattern was noted for basic fibroblast growth factor-2. Fibroblast growth factor-2, which has been previously described as a wound angiogenic factor, exhibited highest levels at POD 0, declining to near serum levels by POD 3. Surgical wound fluid form all time points stimulated marked endothelial cell chemotaxis and induced a brisk neovascular response in the rat corneal micropocket angiogenesis assay. Antibody neutralization of VEGF did not affect the in vitro chemotactic or the in vivo angiogenic activity early wound samples (POD 0). In contrast, VEGF neutralization significantly attenuated both chemotactic activity (mean decrease 76 +/- 13%, P < 0.01) and angiogenic activity (5 of 5 samples affected) of later wound samples (POD 3 and 6). The results suggest a model of wound angiogenesis in which an initial angiogenic stimulus is supplied by fibroblast growth factor-2, followed by a subsequent and more prolonged angiogenic stimulus mediated by VEGF.
Research Interests: Biology, Immunohistochemistry, Macrophages, Medicine, Angiogenesis, and 15 moreAntibodies, Neovascularization, Humans, Female, Pubmed, Animals, Male, Fibroblast Growth Factor, Aged, Middle Aged, ENDOTHELIUM, Exudates and Transudates, fibroblasts, Medical and Health Sciences, and Basic Fibroblast Growth Factor
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Research Interests: Physiology, Biology, Cell Biology, Cornea, Medicine, and 14 moreAngiogenesis, Thrombin, Humans, Mice, Animals, Vascular endothelium, American, Medical Physiology, Epidermal Growth Factor, Epidermal Growth Factor Receptor, Rats, Receptor Tyrosine Kinase, Tyrosine Phosphorylation, and Vascular endothelial growth factors
Research Interests: Engineering, Materials Science, Chemistry, Health Sciences, Biomedical Engineering, and 15 moreTissue Engineering, Science, Biological Chemistry, Medicine, Angiogenesis, Biomedical, Transplantation, Humans, Biomedical Materials, Mice, Animals, Male, Cell Transplantation, Blood Vessels, and Biocompatible Materials
Previous investigations have shown that macrophages play a pivotal role in the induction of angiogenesis in both physiological and pathological settings. This investigation examines the relative production of the angiogenic modulator... more
Previous investigations have shown that macrophages play a pivotal role in the induction of angiogenesis in both physiological and pathological settings. This investigation examines the relative production of the angiogenic modulator thrombospondin-1 (TSP1) by activated and nonactivated monocytes and macrophages. TSP1, a multifunctional extracellular matrix molecule, has been reported recently to inhibit angiogenesis both in vitro and in vivo. To examine the relationship between the level of TSP1 production by macrophages and expression of the angiogenic phenotype, murine monocytelike cells (WEHI-3) and human peripheral blood monocytes were each activated in vitro and examined for TSP1 production and angiogenic activity in rat corneal bioassay. Nonangiogenic monocytes produced low levels of TSP1 messenger RNA. Surprisingly, activated, potently angiogenic monocytes and macrophages exhibited as much as a sixfold increase in steady state TSP1 messenger RNA over unstimulated levels. Biosynthetic labeling studies demonstrated that TSP1 protein secretion increased in conjunction with increased TSP1 messenger RNA levels in angiogenic macrophages. The results demonstrate that activated monocytes and macrophages actively produce the angiogenic modulator TSP1 and suggest that TSP1 production may be a component of the angiogenic phenotype. In addition, the data suggest that the ability of macrophages to mediate angiogenesis results from a complex interplay of positive and negative regulators.
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Research Interests: Health Sciences, Biomedical Engineering, Tissue Engineering, Biology, Cell Biology, and 15 moreMedicine, Angiogenesis, Cell Differentiation, Humans, Vascular endothelium, Bone marrow, Tissue, Endothelial cell, Stromal Cells, Cell Survival, Bone Marrow Cells, Biochemistry and cell biology, Vascular Endothelial Growth Factor, Bone marrow stromal cells, and Vascular endothelial growth factors
The effect of in vivo carcinogen exposure on colony formation and growth of hamster buccal pouch keratinocytes in culture was evaluated at various times after exposing the mucosal surfaces of buccal pouches to initiating regimens of... more
The effect of in vivo carcinogen exposure on colony formation and growth of hamster buccal pouch keratinocytes in culture was evaluated at various times after exposing the mucosal surfaces of buccal pouches to initiating regimens of 7,12-dimethylbenz(a)anthracene (DMBA) or N-methyl-N-benzylnitrosamine (MBN). Keratinocytes were isolated by enzymatic dissociation of intact sheets of buccal pouch epithelium (HBPE) and separated into five fractions of varying buoyant density by isopycnic centrifugation through Percoll. The number of keratinocyte colonies which formed in cultures of unfractionated and fractionated HBPE was evaluated at 1, 2, 3, 4, and 8 weeks after treatment with DMBA and its control vehicle, paraffin oil, and at 6, 8, and 10 weeks after treatment with MBN and its control vehicle, propylene glycol. The rate of colony growth expressed as population doublings per day was determined at these same time periods in unfractionated cultures of carcinogen and control treated HBPE. Unfractionated control (paraffin oil and propylene glycol) cultures gave rise to a uniform number of keratinocyte colonies with a growth rate of approximately 1 population doubling per day at each time period examined. Control cultures of fractionated HBPE exhibited considerable variation in their capacity to form keratinocyte colonies. Fraction 5 cultures which were composed almost exclusively of basaloid cells failed to form colonies. Cultures of unfractionated and fractionated DMBA and MBN-treated HBPE exhibited a marked and persistent suppression in the number and growth of keratinocyte colonies. In addition we observed the development of a morphologically unique type of keratinocyte colony that first emerged in the high density, basaloid-rich fraction 5 cultures, and which subsequently developed in all fractionated and unfractionated HBPE cultures. These unique keratinocyte colonies were never observed in control cultures. These results demonstrate that in vivo exposure of HBPE to DMBA or MBN causes a marked and prolonged suppression in the number and growth of keratinocytes colonies in culture. Furthermore the treatment regimens appeared to induce or select for a population of keratinocytes which persisted in vivo and which exhibited a unique colony morphology when grown in surface culture.
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In order to test the hypothesis that the property of resistance to cytotoxicity is an acquired trait of premalignant oral mucosal epithelium, cell dissociates were prepared from in vivo initiated hamster buccal pouch epithelium (HBPE),... more
In order to test the hypothesis that the property of resistance to cytotoxicity is an acquired trait of premalignant oral mucosal epithelium, cell dissociates were prepared from in vivo initiated hamster buccal pouch epithelium (HBPE), non-initiated HBPE and malignant HBPE cell lines. These cell types were evaluated for resistance to the cytotoxic effects of the inducing carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). A mitoinhibition assay and a clonogenicity assay were used to assess the ability of these cells to replicate or form colonies in the presence of 40 microM DMBA. Replication of primary plated HBPE cells was inhibited by 100% in both assays. PO II, a cell line derived from non-initiated, paraffin-oil-exposed HBPE, was inhibited by 97 and 100% in the mitoinhibition and colony-forming assays respectively. This same cell line, like primary plated HBPE, lacked the transformation-linked traits of angiogenesis and anchorage-independent growth. By contrast, three malignant HBPE cell lines, two derived during long-term culture of DMBA-initiated HBPE, and one from a DMBA-induced HBPE carcinoma, were inhibited by only 34% or less in the assays for resistance to cytotoxicity. Primary cell cultures derived from HBPE initiated in vivo with twice-weekly topical applications of a 0.5% solution of DMBA in paraffin oil, for 3 or 5 weeks, were inhibited to an intermediate degree, indicating the presence of DMBA-resistant cells. In addition, DMBA-resistant cell colonies were observed in cell cultures prepared at 2, 6 and 10 weeks after completing the 5 week initiation regimen. Progenitors of the resistant cells, persisting in vivo for several weeks after initiation, may represent early preneoplastic cell populations in this experimental model.
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Research Interests: Biology, Gene expression, Cell Culture, Cell Division, Biological Sciences, and 15 moreIn Vitro, Humans, Heparin, Collagen, Animals, Biochemical, CHEMICAL SCIENCES, Dermis, Amino Acid Sequence, Fusion Protein, Disintegrin, Dimerization, Cell Size, Medical and Health Sciences, and Immunoglobulin Fc Fragments
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Glioblastoma multiforme is distinguished from its less malignant astrocytoma precursors by intense angiogenesis and frequent loss of tumor suppressor genes on chromosome 10. Here we link these traits by showing that when a wild-type... more
Glioblastoma multiforme is distinguished from its less malignant astrocytoma precursors by intense angiogenesis and frequent loss of tumor suppressor genes on chromosome 10. Here we link these traits by showing that when a wild-type chromosome 10 was returned to any of three human glioblastoma cell lines U251, U87, or LG11, they lost their ability to form tumors in nude mice and switched to an antiangiogenic phenotype, as measured by the inhibition of capillary endothelial cell migration and of corneal neovascularization. This change in angiogenesis was directly due to the increased secretion of a potent inhibitor of angiogenesis, thrombospondin-1, because: (a) neutralizing thrombospondin completely relieved the inhibition; (b) the inhibitory activity of thrombospondin was not dependent on transforming growth factor beta; and (c) chromosome 10 introduction did not alter secreted inducing activity. The inducing activity was dependent on vascular endothelial cell growth factor and had an ED50 of 10 microg/ml in media conditioned by parental cells and 9-13 microg/ml in media conditioned by chromosome 10 revertants. Normal human astrocytes were also antiangiogenic due to secreted thrombospondin. The effect of chromosome 10 on thrombospondin production in vitro was reflected in patient material. Normal brain and lower grade astrocytomas known to retain chromosome 10 stained strongly for thrombospondin, but 12 of 13 glioblastomas, the majority of which lose chromosome 10, did not. These data indicate that the loss of tumor suppressors on chromosome 10 contributes to the aggressive malignancy of glioblastomas in part by releasing constraints on angiogenesis that are maintained by thrombospondin in lower grade tumors.
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Vascular endothelial growth factor (VEGF) is a leading candidate for an endogenous mediator of tumor angiogenesis. Recently, two endothelial cell surface receptors, flk-1 and flt-1, have been shown to mediate the angiogenic activities of... more
Vascular endothelial growth factor (VEGF) is a leading candidate for an endogenous mediator of tumor angiogenesis. Recently, two endothelial cell surface receptors, flk-1 and flt-1, have been shown to mediate the angiogenic activities of VEGF. In this study, we have evaluated whether a soluble VEGF receptor could suppress tumor angiogenesis and thereby inhibit tumor growth. A soluble VEGF receptor was constructed by fusing the entire extracellular domain of murine flk-1 to a six-histidine tag at the COOH terminus (ExFlk.6His). In vitro, recombinant ExFlk.6His protein bound VEGF with high affinity (Kd, 16 nM) and blocked receptor activation in a dose-dependent manner and inhibited VEGF-induced endothelial cell proliferation and migration. ExFlk.6His bound to endothelial cells only in the presence of VEGF, and cell surface cross-linking yielded a high molecular weight complex consistent with the VEGF-mediated formation of a heterodimer between ExFlk.6His and the endogenous VEGF receptor. In vivo, ExFlk.6His potently inhibited corneal neovascularization induced by conditioned media from a rat mammary carcinoma cell line (R3230AC). Moreover, when ExFlk.6His protein was administered into a cutaneous tumor window chamber concomitantly with R3230AC carcinoma transplants, tumor growth was inhibited by 75% (P < 0.005) and vascular density was reduced by 50% (P < 0.002) compared with control-treated tumors. These results demonstrate the potential of ExFlk.6His to inhibit VEGF action by a potent "dominant-negative" mechanism and suggest that targeting VEGF action using a soluble receptor may be an effective antiangiogenic therapy for cancer and other "angiogenic" diseases.
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This study was undertaken to test the hypothesis that deregulated expression of the angiogenic phenotype by tumor cells is due to loss or inactivation of an angiogenesis suppressor gene(s). We used the technique of somatic cell... more
This study was undertaken to test the hypothesis that deregulated expression of the angiogenic phenotype by tumor cells is due to loss or inactivation of an angiogenesis suppressor gene(s). We used the technique of somatic cell hybridization to test the ability of untreated or chemical carcinogen‐initiated hamster pouch keratinocytes, when fused to squamous epithelial neoplasms, to suppress tumor angiogenic activity by assaying hybrid‐conditioned media (CM) in the avascular cornea of rat eyes. A non‐angiogenic keratinocyte line, CL‐2, derived from cultures of untreated epithelium and 3 lines of carcinogen‐initiated keratinocytes, PN3, 5, and 7, of varying angiogenic potential were fused, using polyethylene glycol, to 3 tumorigenic, potently angiogenic, drug‐resistant, hamster Serum‐free 48‐h CM from hybrid clones was prepared and assayed for angiogenic activity in rat corneas. CM from 5 hybrid clones derived from normal × neoplastic keratinocytes failed to induce an angiogenic response in 28 of 29 (97%) corneas tested. In contrast, CM from 4 hybrid clones derived from fusions between carcinogen‐initiated and tumor cells were potently angiogenic in 24 of 25 (96%) corneas tested. Two angiogenesis suppressed hybrids clones were propagated in culture for an extended period of time, to permit chromosome segregation, and were found to re‐express the angiogenic phenotype. These result indicate that angiogenesis is a recessive trait in normal hamster keratinocytes which is regulated in trans in these hybrid cells. It would also appear that loss or inactivation of angiogenesis suppressor function occurs early in the neoplastic process.
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Cigarette smoking could have certain effects on gut microbiota. Some pioneering studies have investigated effects of active smoking on the microbiome in local segments of the digestive tract, while active smoking-induced microbiome... more
Cigarette smoking could have certain effects on gut microbiota. Some pioneering studies have investigated effects of active smoking on the microbiome in local segments of the digestive tract, while active smoking-induced microbiome alterations in the whole digestive tract have not been fully investigated. Here, we developed a rat model of active smoking and characterized the effects of active smoking on the microbiota within multiple regions along the digestive tract. Blood glucose and some metabolic factors levels, the microbial diversity and composition, relative abundances of taxa, bacterial network correlations and predictive functional profiles were compared between the control group and active smoking group. We found that active smoking induced hyperglycemia and significant reductions in serum insulin and leptin levels. Active smoking induced region-specific shifts in microbiota structure, composition, network correlation and metabolism function along the digestive tract. Our ...
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Dental graduates of 2040 will face new and complex challenges. If they are to meet these challenges, dental schools must develop a research and discovery mission that will equip graduates with the new knowledge required to function in a... more
Dental graduates of 2040 will face new and complex challenges. If they are to meet these challenges, dental schools must develop a research and discovery mission that will equip graduates with the new knowledge required to function in a modern health care environment. The dental practitioner of 2040 will place greater emphasis on risk assessment, disease prevention, and health maintenance; and the emerging discipline of precision medicine and systems biology will revolutionize disease diagnosis and reveal new targeted therapies. The dental graduate of 2040 will be expected to function effectively in a collaborative, learning health care system and to understand the impact of health care policy on local, national, and global communities. Emerging scientific fields such as big data analytics, stem cell biology, tissue engineering, and advanced biomimetics will impact dental practice. Despite all the warning signs indicating how the changing scientific and heath care landscape will dra...
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... [14] In vitro and in vivo systems to assess role of CXC chemokines in regulation of angiogenesis. Douglas A. Arenberg, Peter J. polverini, Steven L. Kunkel, Armen Shanafelt, Robert M. Strieter. ... 88 RM Strieter, SL Kunkel, DA... more
... [14] In vitro and in vivo systems to assess role of CXC chemokines in regulation of angiogenesis. Douglas A. Arenberg, Peter J. polverini, Steven L. Kunkel, Armen Shanafelt, Robert M. Strieter. ... 88 RM Strieter, SL Kunkel, DA Arenberg, MD Burdick, and PJ Polverini, Biochem. ...
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In Phase 1 of the “Advancing Dental Education in the 21st Century” project, research was conducted and published on a number of serious challenges facing dental and allied dental education, both presently and projected to 2040. Those... more
In Phase 1 of the “Advancing Dental Education in the 21st Century” project, research was conducted and published on a number of serious challenges facing dental and allied dental education, both presently and projected to 2040. Those findings informed the strategic analysis and recommendations developed in Phase 2 of the project. This report provides an overview of the Phase 2 conclusions and presents recommendations to address the challenges identified. The recommendations propose ways to educate a workforce prepared to meet the oral health needs of the population; develop a sustainable economic model that allows schools to meet their education, research, and service missions; make dental and allied dental education and practice an integral part of the larger health education and delivery systems; and keep dentistry advancing as a “learned” profession. This report begins with an Executive Summary and then presents the strategic analysis of challenges facing dental schools and allie...
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Vascular endothelial growth factor (VEGF) has been shown to be a potent mediator of angiogenesis that functions as a survival factor for endothelial cells by up-regulating Bcl-2 expression. We have recently reported that human dermal... more
Vascular endothelial growth factor (VEGF) has been shown to be a potent mediator of angiogenesis that functions as a survival factor for endothelial cells by up-regulating Bcl-2 expression. We have recently reported that human dermal microvascular endothelial cells (HDMECs) seeded in biodegradable sponges and implanted into severe combined immunodeficient (SCID) mice organize into functional human microvessels that transport mouse blood cells. In this study, we implanted sponges seeded with OSCC-3 (oral squamous cell carcinoma) or SLK (Kaposi's sarcoma) together with endothelial cells into SCID mice to generate human tumors vascularized with human microvessels. This model system was used to examine the role of both endothelial cell Bcl-2 and the proangiogenic chemokine interleukin-8 (IL-8) on tumor growth and intratumoral microvascular density. Coimplantation of HDMECs overexpressing Bcl-2 (HDMEC-Bcl-2) and tumor cells resulted in a 3-fold enhancement of tumor growth when compared with the coimplantation of control HDMECs and tumor cells. This was associated with increased intratumoral microvascular density and enhanced endothelial cell survival. To determine whether the enhanced neovascularization mediated by Bcl-2 overexpression in endothelial cells was influenced by the synthesis of endogenous mediators of angiogenesis, we screened these cells for expression of VEGF, basic fibroblast growth factor (bFGF), and IL-8 by ELISA. HDMEC-Bcl-2 cells and VEGF-treated HDMECs exhibited a 15-fold and 4-fold increase, respectively, in the expression of the proangiogenic chemokine IL-8 in vitro, whereas the expression of VEGF and bFGF remained unchanged. Transfection of antisense Bcl-2 into HDMECs blocked VEGF-mediated induction of IL-8. Conditioned media from HDMEC-Bcl-2 induced proliferation and sprouting of endothelial cells in vitro and neovascularization in rat corneas. Anti-IL-8 antibody added to HDMEC-Bcl-2 conditioned media markedly reduced the potency of these responses. SCID mice bearing VEGF-producing tumor implants that were treated with anti-lL-8 antibody exhibited a 43% reduction in microvessel density and a 50% reduction in tumor weight compared with treatment with a nonspecific antibody. These results demonstrate that the up-regulation of Bcl-2 expression in endothelial cells that constitute tumor microvessels enhances intratumoral microvascular survival and density and accelerates tumor growth. Furthermore, endothelial cells that overexpress Bcl-2 have more angiogenic potential than control cells, and IL-8-neutralizing antibodies attenuate their angiogenic activity in vitro and in vivo.
Research Interests: Cancer, Biology, Density, Cancer Research, Medicine, and 15 moreGene expression, Angiogenesis, Cell Division, Antibodies, Humans, Mice, Animals, Cell Transplantation, Endothelial cell, Cell Proliferation, Blood cells, Gene Expression Regulation, Interleukin, Conditioned media, and Basic Fibroblast Growth Factor
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The Unfolded Protein Response (UPR) is activated when the endoplasmic reticulum (ER) in tumor cells is subjected to environmental stress. We and others have previously shown that the eIF2α- PERK-ATF4 pathway, one of three of UPR pathways... more
The Unfolded Protein Response (UPR) is activated when the endoplasmic reticulum (ER) in tumor cells is subjected to environmental stress. We and others have previously shown that the eIF2α- PERK-ATF4 pathway, one of three of UPR pathways is involved in tumor angiogenesis by transcriptionally regulating the production of angiogenic mediators such as VEGF. However, role of other UPR pathways in tumor angiogenesis still remains to be elucidated. In this study we examined the role of the IRE1-XBP1 UPR pathway in promoting production of tumor-derived proangiogenic mediators. Upon ER stress IRE1 splices XBP1 into an active transcription factor that induces expression of several target genes. We used the gene-silencing approach in the oral squamous carcinoma cell line UM-SCC-81B to determine the effects of XBP1 knockdown on key angiogenic mediators. We were able to achieve over 80% knockdown of XBP1. mRNA levels of both EDEM1 and Grp78, downstream targets of XBP1 were also significantly inhibited confirming an efficient knockdown. UM-SCC-81B control cells as well as UM-SCC-81B-XBP1 knockdown cells were initially treated with low glucose (5mM) for 24 h to induce UPR. Next, mRNA and protein levels of VEGF were determined using Real-Time PCR and ELISA respectively. We observed a 45% decrease in VEGF mRNA levels and around 36% decrease in VEGF protein levels of UM-SCC-81B-XBP1 knockdown cells upon ER stress. Additionally, we detected a significant decrease in the transcription of several other key angiogenic mediators such as FGF2, IL6, IL8 and CTGF (p&lt;0 .05) in UM-SCC-81B-XBP1 knockdown cells compared to control cells. These results suggest that the IRE1-XBP1 pathway of the UPR promotes tumor angiogenesis through modulating expression of proangiogenic mediators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4993. doi:1538-7445.AM2012-4993
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Thrombospondin-1 (TSP1) is a potent natural inhibitor of angiogenesis. Although TSP1 has been reported to induce endothelial cell apoptosis in vitro and to downregulate neovascularization in vivo, the molecular mechanisms that link these... more
Thrombospondin-1 (TSP1) is a potent natural inhibitor of angiogenesis. Although TSP1 has been reported to induce endothelial cell apoptosis in vitro and to downregulate neovascularization in vivo, the molecular mechanisms that link these two processes have yet to be established. Here we report that TSP1 mediates endothelial cell apoptosis and inhibits angiogenesis in association with increased expression of Bax, decreased expression of Bcl-2, and processing of caspase-3 into smaller proapoptotic forms. The ability of TSP1 to induce both endothelial cell apoptosis in vitro and to suppress angiogenesis in vivo was blocked by the caspase-3 inhibitor z-DEVD-FMK. TSP1 also attenuated VEGF-mediated Bcl-2 expression in endothelial cells in vitro and angiogenesis in vivo. Furthermore, TSP1 induced endothelial cell apoptosis and inhibited neovascularization in sponge implants in SCID mice. We conclude that TSP1 induces endothelial cell apoptosis and inhibits neovascularization by altering the profile of survival gene expression and activating caspase-3.
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Figure S1. Generation of HLA-A*02-restricted EGFR-specific CD8+ cytotoxic T lymphocytes; Figure S2. SOX2 inhibits IFN-I signaling by promoting autophagy-mediated degradation of STING; Figure S3. Validation of C57BL/6-syngeneic mouse... more
Figure S1. Generation of HLA-A*02-restricted EGFR-specific CD8+ cytotoxic T lymphocytes; Figure S2. SOX2 inhibits IFN-I signaling by promoting autophagy-mediated degradation of STING; Figure S3. Validation of C57BL/6-syngeneic mouse squamous cell carcinoma cells; Figure S4. Characterization of MOC2-E6/E7 tumors; Figure S5: Clinical and immunological correlations of SOX2 expression in human HNSCC; Figure S6. SatVax (Q19D; Q15L) effectively controls tumor growth in larger established tumors and improves survival; Figure S7. Treatment schedule and individual tumor growth curves of Sox2-positive tumors
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List of deferentially expressed genes in HNSCC cancer cells resistant to immune killing
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This file includes Supplementary Tables S2-S4 and captions for all supplementary tables.
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Neovascularization is a limiting factor in tumor growth and progression. It is well known that changes in the tumor microenvironment, such as hypoxia and glucose deprivation (GD), can induce VEGF production. However, the mechanism linking... more
Neovascularization is a limiting factor in tumor growth and progression. It is well known that changes in the tumor microenvironment, such as hypoxia and glucose deprivation (GD), can induce VEGF production. However, the mechanism linking GD to tumor growth and angiogenesis is unclear. We hypothesize that GD induces the angiogenic switch in tumors through activation of the unfolded protein response (UPR). We report that UPR activation in human tumors results in elevated expression of proangiogenic mediators and a concomitant decrease in angiogenesis inhibitors. cDNA microarray results showed that GD-induced UPR activation promoted upregulation of a number of proangiogenic mediators (VEGF, FGF-2, IL-6, etc.) and downregulation of several angiogenic inhibitors (THBS1, CXCL14, and CXCL10). In vitro studies revealed that partially blocking UPR signaling by silencing protein kinase RNA–like ER kinase (PERK) or activating transcription factor 4 (ATF4) significantly reduced the production of angiogenesis mediators induced by GD. However, suppressing the alpha subunit of hypoxia-inducible factors had no effect on this process. Chromatin immunoprecipitation (ChIP) confirmed binding of ATF4 to a regulatory site in the VEGF gene. In vivo results confirmed that knockdown of PERK in tumor cells slows down tumor growth and decreases tumor blood vessel density. Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. Cancer Res; 72(20); 5396–406. ©2012 AACR.