Influence Tumor Cell Research Articles

Activation of NF-kappa B Signaling Promotes Growth of Prostate Cancer Cells in Bone

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation.

Efficient tumor targeting by anaerobic butyrate-producing bacteria

Butyrate as an important short chain fatty acid has been shown to affect different kinds of cancer cells. Butyrate exerts its anti-cancerous effects by several mechanisms and has lead to successful outcomes in phase I and II clinical trials. Moreover, since solid tumors grow rapidly, multiple regions of hypoxia and anoxia forms within them that provide good niches for the growth of anaerobic bacteria. It has been shown that bacterial tumor targeting is an applicable strategy for tumor-selective therapy. Therefore, we propose that nonpathogenic anaerobic butyrate-producing bacteria may be a versatile tool in tumor therapy as they can grow in anoxic and hypoxic regions of tumors and influence tumor cells by producing butyric acid. Moreover, this approach may overcome the existing problems of butyrate delivery to the sites of tumor and enhance its bioavailability. Also reversion of cancer drug resistance by butyrate will be plausible. Tumor targeting with nonpathogenic anaerobic bacteria with a higher capacity to produce butyrate could be the focus of future research.

Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors

Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst2. Pasireotide is a sst multireceptor ligand with affinity for sst1, sst2, sst3 and sst5 and this broader binding profile may translate into a higher efficacy with respect to suppression of hormone production and cell growth in certain tumors. Experimental animal studies and in vitro studies with cultured tumor cells have shown that pasireotide strongly suppresses growth hormone and adrenocorticotropin production. In addition, pasireotide can influence tumor cell growth via effects on apoptosis and angiogenesis. In this review, the role of somatostatin receptors in pituitary and neuroendocrine tumors is briefly discussed followed by an overview of possible applications of pasireotide based on recent trials in patients with acromegaly, Cushing's disease and neuroendocrine tumors.

Tumor Therapy with Amanita phalloides: Remission of a Tumor Disease and Dietary Effect of Sugar

Molecular events that cause tumor formation upregulate a number of HOX genes, called switch genes, encoding for RNApolymeraseII transcription factors. Thus, RNApolymeraseII is used to full extent in tumor cells but not in somatic cells. Amanita phalloides contains amanitin, inhibiting RNApolymeraseII. Application of Amanita phalloides influences tumor cell (but not normal cell) activity. Dilutions of Amanita phalloides are applied to a patient with both, colon carcinoma and thyroid carcinoma. Monitoring tumormarkers, different doses of Amanita are applied. After two years of stabilization, somatic investigations and imaging methods reveal complete remission. Change of dietary practice with the addition of daily 70 gram sugar lead to increase of tumormarker values. Following dietary without sugar and reduced carbohydrates decrease tumormarker values. With sugar, tumor activity increase despite Amanita tumor therapy, therefore, poor carbohydrate diet supports the therapy

SRPK1 Dissimilarly Impacts on the Growth, Metastasis, Chemosensitivity and Angiogenesis of Glioma in Normoxic and Hypoxic Conditions

Glioma is among the ten most common causes of cancer-related death and has no effective treatment for it, so we are trying to find a new target for anticancer treatment. This study investigates the different expression of SRPK1 as a novel protein in glioma, which can influence tumor cells biological characteristics in normoxic and hypoxic environment. The expression levels of SRPK1 protein in glioma cell lines transfected with siSRPK1 or not were examined using immunofluorescence, RT-PCR and Western blot analysis, respectively. The impact of SRPK1 on the biological characteristics of U251 cells was further studied using methylthiazol tetrazolium assays, flow cytometry, and Transwell invasion chamber assays. The results showed that knockdown of SRPK1 inhibited tumor cells growth, invasion and migration in normoxic condition, but portion of the effect could be reversed in hypoxia. SRPK1 expression was induced in glioma cells by DDP treated, but not TMZ, in both normoxia and hypoxia conditions. We propose SRPK1 as a new molecular player contributing to the early treatment of glioma.

Abstract B65: Biomarker effects of an oral green tea extract, Polyphenon E, in women with a history of hormone receptor-negative breast cancer

Abstract Background: Observational studies have correlated green tea intake with reduced breast cancer risk. In preclinical studies, the main polyphenol of green tea, epigallocatechin-3-gallate (EGCG), inhibits growth factors, such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which influence tumor cell growth, migration, and invasion. We conducted an ancillary study using archived serum and urine from a completed phase IB randomized, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in women with hormone receptor (HR)-negative breast cancer. The objective was to understand the effects of Poly E on potential biomarkers of breast cancer risk. Methods: Forty women with stage I-III HR-negative breast cancer who completed adjuvant treatment were randomized using an adaptive trial design to Poly E 400 mg (n = 16), 600 mg (n = 11), 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, 2, 4, and 6 months. Biologic endpoints included oxidative damage (urine 8-oxoG and isoprostane, plasma carbonyls), inflammatory (serum C-reactive protein [CRP], urine prostaglandin E2 metabolite [PGE-M]), growth factor (serum VEGF, HGF), and lipid (total cholesterol, triglycerides) biomarkers, as well as total urinary tea polyphenols. Results: From July 2007 to Sept 2009, 40 women were enrolled from 4 sites. During the intervention, 5 women developed a dose-limiting toxicity which required stopping study drug, 4 were lost to follow-up, and complete biomarker data was available for 34 participants (26 Poly E, 8 placebo). Concentration of total urinary tea polyphenol metabolites increased from baseline by an average of 10-fold in the Poly E group (all dose levels combined) compared to placebo (p = 0.001). Within the Poly E group, the mean decrease from baseline in serum VEGF was statistically significant at months 2 (11.5%, p = 0.02) and 4 (13.9%, p = 0.04). However, these changes were not significant when compared to placebo. At 2 months, mean serum HGF levels decreased by 12.6% for Poly E compared to a 6.3% increase for placebo (p = 0.04). This trend persisted at 4 and 6 months, but was no longer statistically significant. With Poly E treatment, there was a non-significant trend toward a decrease from baseline in serum cholesterol at 2, 4, and 6 months. No significant differences were observed in the biomarkers of oxidative damage (urine 8-oxoG and isoprostane, plasma carbonyls) or inflammation (serum CRP, urine PGE-M) after treatment with Poly E compared to placebo. Discussion: We demonstrated a significant reduction in serum HGF and a favorable decline in serum VEGF and total cholesterol during a 6-month intervention of Poly E in women with breast cancer. Given the small sample size and lack of adjustment for multiple comparisons, these results need to be confirmed in a larger study. Nevertheless, these findings are consistent with published results from short-term intervention trials of Poly E. This suggests potential mechanisms of action of green tea in angiogenesis, growth factor signaling, and metabolic pathways. Citation Format: Katherine D. Crew, Kimberly A. Ho, Powel Brown, Heather Greenlee, Therese B. Bevers, Banu Arun, Clifford Hudis, Heather L. McArthur, Jenny Chang, Mothaffar Rimawi, Lana Vornik, Terri L. Cornelison, James Cardelli, Regina M. Santella, Antai Wang, Scott M. Lippman, Dawn L. Hershman. Biomarker effects of an oral green tea extract, Polyphenon E, in women with a history of hormone receptor-negative breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B65.

Impact of CCL2 and Its Receptor CCR2 Gene Polymorphism in North Indian Population: A Comparative Study in Different Ethnic Groups Worldwide

Chemokine are small, inducible pro-inflammatory cytokines involved in many biological processes, such as migration of leukocytes, atherosclerosis, angiogenesis, tumor growth, and metastasis. Chemokine are also known to influence tumor cell's activity. Specifically, tumor cells express chemokine receptors in a non random manner suggesting a role of chemokine in metastatic destination of tumor cells. The present study was conducted to determine distribution of (Chemokine receptor 2) CCR2 V64I, Chemokine ligand 2 CCL2 I/D, and CCL2 2518 A>G gene polymorphisms in North Indian population and compare with different populations globally. Polymerase chain reaction (PCR)-based analysis was conducted in 200 normal healthy individuals of similar ethnicity. Allelic frequencies in wild type (GG) of CCR2 V64I G>A were 63% G; CCL2 I/D 42% II; CCL2 2518 A>G 40.5% A. The minor variant allele frequency in our population was as follows: 19.5% for CCR2 V64I, 35.5% for CCL2 I/D, 35.3% for CCL2 2518 A>G. We further compared frequency distribution for these genes with various published studies in different ethnicity. Our results suggested that frequency in chemokine genes exhibit distinctive pattern in India that could be attributed to ethnicity variation. This could assist in high-risk screening of human exposed to environmental carcinogens and cancer predisposition in different ethnic groups. Thus, they signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.

The Primacy of β1 Integrin Activation in the Metastatic Cascade

After neoplastic cells leave the primary tumor and circulate, they may extravasate from the vasculature and colonize tissues to form metastases. β1 integrins play diverse roles in tumorigenesis and tumor progression, including extravasation. In blood cells, activation of β1 integrins can be regulated by “inside-out” signals leading to extravasation from the circulation into tissues. However, a role for inside-out β1 activation in tumor cell metastasis is uncertain. Here we show that β1 integrin activation promotes tumor metastasis and that activated β1 integrin may serve as a biomarker of metastatic human melanoma. To determine whether β1 integrin activation can influence tumor cell metastasis, the β1 integrin subunit in melanoma and breast cancer cell lines was stably knocked down with shRNA and replaced with wild-type or constitutively-active β1. When tumor cells expressing constitutively-active β1 integrins were injected intravenously into chick embryos or mice, they demonstrated increased colonization of the liver when compared to cells expressing wild-type β1 integrins. Rescue expression with mutant β1 integrins revealed that tumor cell extravasation and hepatic colonization required extracellular ligand binding to β1 as well as β1 interaction with talin, an intracellular mediator of integrin activation by the Rap1 GTPase. Furthermore, shRNA-mediated knock down of talin reduced hepatic colonization by tumor cells expressing wild-type β1, but not constitutively-active β1. Overexpression in tumor cells of the tumor suppressor, Rap1GAP, inhibited Rap1 and β1 integrin activation as well as hepatic colonization. Using an antibody that detects activated β1 integrin, we found higher levels of activated β1 integrins in human metastatic melanomas compared to primary melanomas, suggesting that activated β1 integrin may serve as a biomarker of invasive tumor cells. Altogether, these studies establish that inside-out activation of β1 integrins promotes tumor cell extravasation and colonization, suggesting diagnostic and therapeutic approaches for targeting of β1 integrin signaling in neoplasia.

Tumor cell migration in complex microenvironments

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable.

IFNs, ISGylation and cancer: Cui prodest?

IFNs are cytokines that segregate viral infections, modulate the immune responses and influence tumor cells survival. These options are under the control of ISGs (Interferon Stimulated Genes) which expression is propelled by IFNs. To the ISGs family belong all the components of the molecular machinery that modifies proteins by the addition of the ubiquitin-like protein ISG15, in a process known as ISGylation. Despite alterations in the components of this machinery are frequently observed in cancer, the contribution of ISG15 and of ISGylation to tumor growth and resistance to chemotherapy is unclear and debated. With the aim of elucidating this point, in this review we have discussed about recent data pointing to a dysregulation of the IFN signaling and the ISGylation system in cancer.

Combined EGFR and VEGFR versus single EGFR signaling pathways inhibition therapy for NSCLC: a systematic review and meta-analysis.

BackgroundLung cancer is a heterogeneous disease with multiple signaling pathways influencing tumor cell survival and proliferation, and it is likely that blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Whether combined inhibition therapy has greater anti-tumor activity than single inhibition therapy is a matter of debate. Hence, a meta-analysis comparing therapy inhibiting both VEGFR and EGFR signaling pathways with that inhibiting EGFR signaling pathway alone was performed.Methodology and Principal FindingsWe searched PubMed, EMBASE database and the proceedings of major conferences for relevant clinical trials. Outcomes analyzed were objective tumor response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Besides, subgroup analyses were performed to investigate whether the combined inhibition therapy is best performed using combination of selective agents or a single agent with multiple targets.Six trials recruiting 3,302 patients were included in the analysis. Combined inhibition therapy was associated with a 3% improvement in OS as compared with single-targeted therapy, but this difference was not statistically significant (HR, 0.97; 95% CI, 0.89–1.05; P = 0.472). Patients receiving combined inhibition therapy had significant longer PFS than the group with single-targeted therapy (HR, 0.80; 95% CI, 0.67–0.95; P = 0.011). There was no difference in the ORR between the groups (OR, 1.44; 95% CI, 0.95–2.18; P = 0.085). Subgroup analysis revealed that combined inhibition therapy using combination regimens was associated with statistically significant improvement in both ORR and PFS. Toxicity was greater in combined inhibition therapy.ConclusionsThere is no evidence to support the use of combined inhibition therapy in unselected patients with advanced NSCLC. However, given the significant advantage in ORR and PFS, combined inhibition therapy using combination regimens may be considered for further evaluation in subsets of patients who may benefit from this treatment.

Fibroblast EXT1-Levels Influence Tumor Cell Proliferation and Migration in Composite Spheroids

BackgroundStromal fibroblasts are important determinants of tumor cell behavior. They act to condition the tumor microenvironment, influence tumor growth, support tumor angiogenesis and affect tumor metastasis. Heparan sulfate proteoglycans, present both on tumor and stromal cells, interact with a large number of ligands including growth factors, their receptors, and structural components of the extracellular matrix. Being ubiquitously expressed in the tumor microenvironment heparan sulfate proteoglycans are candidates for playing central roles in tumor-stroma interactions. The objective of this work was to investigate the role of heparan sulfate expressed by stromal fibroblasts in modulating the growth of tumor cells and in controlling the interstitial fluid pressure in a 3-D model.Methodology/Principal FindingsWe generated spheroids composed of fibroblasts alone, or composite spheroids, composed of fibroblasts and tumor cells. Here we show that stromal fibroblasts with a mutation in the heparan sulfate elongating enzyme Ext1 and thus a low heparan sulfate content, formed composite fibroblast/tumor cell spheroids with a significant lower interstitial fluid pressure than corresponding wild-type fibroblast/tumor cell composite spheroids. Furthermore, immunohistochemistry of composite spheroids revealed that the cells segregated, so that after 6 days in culture, the wild-type fibroblasts formed an inner core and the tumor cells an outer layer of cells. For composite spheroids containing Ext1-mutated fibroblasts this segregation was less obvious, indicating impaired cell migration. Analysis of tumor cells expressing the firefly luciferase gene revealed that the changes in tumor cell migration in mutant fibroblast/tumor cell composite spheroids coincided with a lower proliferation rate.Conclusions/SignificanceThis is the first demonstration that stromal Ext1-levels modulate tumor cell proliferation and affect the interstitial fluid pressure in a 3-D spheroid model. Learning how structural changes in stromal heparan sulfate influence tumor cells is essential for our understanding how non-malignant cells of the tumor microenvironment influence tumor cell progression.

Human Adipose Tissue Macrophages Display Activation of Cancer-related Pathways

Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.

Toll‐like receptor‐4 agonist inhibits motility and invasion of hepatoblastoma HepG2 cells in vitro

Expression of toll-like receptor-4 (TLR4) on tumor cells is known to mediate innate immune responses that influence tumor cell growth and migration. This study aimed to characterize TLR4 expression and elucidate its functional significance in human hepatoblastoma (HB) cells. Immunohistochemistry (IHC) was used to determine TLR4 expression level and its distribution pattern in HB liver tissues. Transcripts of tumor necrosis factor (TNF)-α, interleukin (IL)-8, matrix metalloproteinase (MMP)-2, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 in HB HepG2 cells with lipopolysacharide (LPS) treatment were measured by quantitative PCR. Soluble cytokines and peptides in conditioned media were measured by ELISA. MMP-2 activity was determined by using gelatin zymography. Cell motility and invasiveness was determined using wound healing migration and Matrigel invasion assays, respectively. TLR4 IHC staining demonstrated that TLR4 overexpression in HB liver tissues dramatically vanished after chemotherapy. In vitro study using an HB cell line, HepG2, showed that TLR4 agonist, LPS, significantly decreased transcripts of IL-8 and TNF-α, but did not affect MMP-13 mRNA level. By contrast, LPS only down-regulated IL-8 production and MMP-2 gelatinolytic activity. The latter might be in part due to the increased levels of MMP-2/TIMP-2 complex in conditioned media, thus leading to the decreased motility and invasiveness of HepG2 cells. HB cells overexpress TLR4, whereas TLR4 agonistic treatment inhibits migration and invasion of HB HepG2 cells. These findings suggest that TLR4 signaling pathway is a potential therapeutic target for control of HB tumor progression.

New Wrinkle Between Cancer and Blood Coagulation: Metastasis and Cleavage of von Willebrand Factor by ADAM28

New Wrinkle Between Cancer and Blood Coagulation: Metastasis and Cleavage of von Willebrand Factor by ADAM28

Diseminación tumoral perioperatoria. 2. Efectos de la anestesia y analgesia

There has been growing concern over the last few years on the effect that the anaesthetic drugs used during oncological surgery could have on long-term tumour progression. In laboratory studies, it has been observed how some substances used during the anaesthetic procedure influence tumour immunosurveillance, cell proliferation or tumour angiogenesis processes. The possible clinical relevance of the anaesthetic technique used as regards long-term tumour progression and survival is still to be determined. However, based on retrospective studies, it appears that those anaesthetic techniques combined with the use of regional anaesthesia and analgesia may be beneficial compared to those that are maintained on the use of opioids. Further research should help to clarify the long-term clinical relevance of the anaesthetic process during oncological surgery.

Abstract 1492: Eavesdropping of crosstalk between adipose stem cells (ASC) and ovarian cancer cells

Abstract Background Adipose tissue contains a population of multipotent adipose stromal cells (ASC) which migrate into tumors and form supportive tumor stroma elements. ASCs release various growth factors, cytokines and metabolites that influence on physiochemical nature of the local environment. Ovarian cancer cells have a predilection for metastasis in omentum, the primary repository for visceral adipose. The effects of omental derived adipose stem cells (O-ASC) and subcutaneous tissue derived adipose stem cells (SC-ASC) on ovarian cancer biology including ovarian cancer proliferation, gene expression and response to chemotherapy were investigated. Methods and Results Luciferase labelled ovarian carcinoma cells (OVCA 429) were co-cultured with O-ASC, SC-ASC and control fibroblast line Wi38. Significantly higher levels of luciferase activity was detected when ovarian carcinoma cells were co-cultured with O-ASC than with SC-ASC and Wi38 (3470.4 RLU vs 1253.2 RLU, p=<0.005). Moreover, co-culture of 429 cells with ASCs in presence of different concentrations of Taxol revealed that O-ASC influence tumor cell chemosensitivity. Additionally, O-ASC promoted formation of significantly more ovarian carcinoma tumorispheres which were more closer associated to each other than those created in sphere medium only. To identify differentially expressed genes in O-ASC and SC-ASC, we performed microarray experiments (NimbleGen platform) which were analyzed using Ingenuity Pathway Analysis (IPA) software. The highest expressed genes were connected with growth, proliferation and development of cells and most of the proteins coded by these genes were localized in the extracellular space, plasma membrane or exosomes (CALR, UNC5B in O-ASC or COL1A2, FN1 in SC-ASC). We also performed ELISA assays focused on release of growth factors which revealed that O-ASC and SC-ASC secrete more VEGF (1678 pg/ml) and FGF (29 pg/ml) compared to control cells Wi38 (114 pg/ml and 2.7 pg/ml respectively). Chemokine SDF-1α was also secreted in high level by O-ASC S1 (1537 pg/ml) but SC-ASC released only 187 pg/ml relative to Wi38 (706 pg/ml) which indicates that these two types of adipose stem cells can create different surrounding environment. Summary O-ASC cells have unique tumor promoting effects and create specific environmental niche by releasing growth factors, cytokines and other factors which can stimulate ovarian cancer cells to grow faster and clump together. ASC may also influence protection of ovarian cancer from toxicity of chemotherapeutics. The knowledge about microenvironmental crosstalk between normal stem cells and tumor cells can contribute in the development of new treatment to prevent metastasis of ovarian cancer and make them vulnerable to chemotherapy. 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 1492. doi:1538-7445.AM2012-1492

Abstract 387: PEDF binds to IL- 10 receptor in the absence of IL-10 and inhibits melanoma tumor growth

Abstract Macrophages exist within the tumor microenvironment and play an important role in influencing tumor cell growth, angiogenesis and cancer progression. The interaction between macrophages, tumor cells, and endothelial cells occurs largely through cytokine secretion and detection by tumor associated macrophages (TAM). In this study, we investigate the role of interleukin-10 (IL-10) and pigment epithelial derived factor (PEDF) in the macrophage-tumor interaction. In an explant model of melanoma, tumor growth was significantly reduced in IL-10 knockout mice. Media from IL-10 deficient macrophages significantly inhibited tumor cell proliferation when compared to media from wild-type macrophages. Interestingly, expression of the anti-tumor and anti-angiogenic cytokine PEDF was increased in IL-10 knockout macrophages. Media of IL-10 KO macrophages treated with recombinant IL-10 (rIL-10) and anti-PEDF failed to inhibit tumor cell proliferation. Neutralization of PEDF in IL-10 KO mice restored tumor growth in these mice. To further explore the molecular mechanisms of the interaction between PEDF, IL-10 and IL-10 receptor, IL-10 receptor binding of PEDF was evaluated in presence or absence of rIL-10. PEDF binds to IL-10 receptor only in the absence of competing rIL-10. Taken together these studies show a novel interaction between PEDF and the IL-10 receptor and suggest that the anti-tumor activity of PEDF can be significantly enhanced by reducing IL-10 levels. 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 387. doi:1538-7445.AM2012-387

Abstract 1557: High mobility group box 1 secretion supports tumor progression of human malignant mesothelioma

Abstract Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer, often associated with exposure to asbestos and erionite. Prognosis is poor, due to late-stage diagnosis and resistance to current conventional therapies. We previously showed that high-mobility group box-1 protein (HMGB1), a damage-associated molecular pattern (DAMP) protein, is involved in the early stages of mesothelial cell transformation. Here we show that HMGB1 establishes an autocrine circuit in MM cells influencing tumor cell proliferation and survival. MM cells express HMGB1 at high levels and secrete HMGB1 into the extracellular space. Accordingly, HMGB1 levels in MM patients’ sera are significantly higher than in those of healthy individuals. In addition, motility, survival and anchorage-independent growth of HMGB1-secreting MM cells were inhibited in vitro by a monoclonal antibody (mAb) against HMGB1, by the recombinant HMGB1 competitive antagonist BoxA and by antibodies against the receptor for advanced glycation end products (RAGE). Inhibition of HMGB1 reduced the growth of MM xenografts in SCID mice and extended survival. Our findings indicate that MM cells become “addicted” to HMGB1 and that targeting HMGB1 can be a promising novel therapeutic approach for MM. 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 1557. doi:1538-7445.AM2012-1557

Role of hyaluronan synthase 2 to promote CD44‐dependent oral cavity squamous cell carcinoma progression

CD44 is a transmembrane receptor found on many different benign and malignant cells. Hyaluronan (HA), a major component of the extracellular matrix, is the primary ligand for CD44 receptors. In cancer cells, HA interaction with CD44 promotes multiple signaling pathways that influence tumor cell progression behaviors in a variety of solid tumors. Increasing evidence indicates that HA and CD44 signaling play an important role in oral cavity squamous cell carcinoma progression. HA is primarily synthesized by hyaluronan synthases, and the current study investigated the role of hyaluronan synthase 2 (HAS 2) in oral cavity carcinoma progression behaviors. Analysis of HAS 2 mRNA and protein expression, HA production, and HAS 2-mediated tumor cell proliferation and migration behaviors with and without HAS 2 suppression were carried out on 2 established oral cavity cancer cell lines. Immunohistochemical analysis of HAS 2 and CD44 expression in oral cavity carcinoma tumor specimens was performed. HAS 2 was expressed in the 2 oral cancer cell lines, HSC-3 and SCC-4. Suppression of HAS 2 expression resulted in CD44-dependent decreased tumor cell migration, decreased tumor cell growth, and increased cisplatin sensitivity, suggesting the importance of tumor cell HA production to promote in vitro tumor progression behaviors in oral cancer cells. Increased HAS 2 expression in oral cavity carcinoma clinical specimens was associated with poor clinicopathologic characteristics and worse disease-free survival. HAS 2 may be a potential therapeutic target for the treatment of oral cavity cancer.