Growth Factor For Tumor Cells Research Articles

S3663 Refractory Hypoglycemia Induced by a Gastrointestinal Stromal Tumor Secreting Insulin-Like Growth Factor-2

Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome that leads to the release of insulin-like growth factor-2 (IGF-2). It is commonly associated with tumors of mesenchymal origin like gastrointestinal stromal tumors (GIST). Case Description/Methods: A 62-year-old male, with a past medical history of recently diagnosed GIST was started on imatinib but stopped taking it one month ago pending surgical evaluation, presents with altered mental status due to severe hypoglycemia. The patient had no prior history of diabetes or adrenal insufficiency. The patient's repetitive finger sticks glucose remained persistently low even after good oral intake and two D50 pushes. Urine toxicology and drug screen for sulfonylureas were negative. Laboratory investigations showed reduced levels of insulin, C-peptide, and insulin-like growth factor-1 (IGF-1), but his IGF-2 was increased. Endocrinology was consulted for refractory hypoglycemia; recommended to start D10 fluids in the setting of resistant low blood glucose and start octreotide and steroids. Insulinoma was unlikely as insulin and C-peptides were low. CT chest/abdomen/pelvis shows grossly unchanged gastric GIST, measuring 25 × 19.6 × 11.4 cm with no evidence of metastatic disease in the abdomen or pelvis (Figure 1A). Esophagogastroduodenoscopy (EGD) demonstrated large, bilobed subepithelial mass measuring 10-15 cm with an area of ulceration within the mass (Figure 1B) followed up with Endoscopic ultrasound (EUS) demonstrating subepithelial lesion was found likely arising from the fundus, lesser curve and body of the stomach, layer of origin could not be determined on due to the large size of the mass (Figure 1C). Oncology was consulted for further management of malignancy; imatinib was resumed and referred for surgical evaluation for tumor removal. Discussion: IGF-II acts as an autocrine growth factor in tumor cells therefore, it is highly likely that IGF-II will be high in case of high tumor bulk and making them at high risk of developing NICTH. In patients diagnosed with GIST with hypoglycemic symptoms, we should consider IGF-II secreting GIST in addition to insulinoma especially in bulky tumors.Figure 1.: A: CT scan abdomen/pelvis with contrast showing large soft tissue density mass inseparable from the lesser curvature of the stomach marked with asterisk. B: EGD findings consistent with a large, bilobed subepithelial mass measuring 10-15 cm with an area of ulceration within the mass (seen best on retroflexion) was found on the lesser curvature of the stomach along the anterior wall of the stomach. C: Endoscopic US findings showed A 43.0 mm × 77.8 mm subepithelial lesion was found likely arising from the fundus, lesser curve and body of the stomach s/p FNB × 4. The lesion was hypoechoic and had some cystic spaces within it in some areas. Sonographically, the lesion appeared to originate from the stomach, but the wall layers could not be determined due to the large size of the mass.

5-HT7 Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells.

IntroductionBecause only a small portion of NSCLC (non-small-cell lung cancer) patients benefit from molecular targeted therapy or immunotherapy and do not develop therapeutic resistance, continued research on new targets is warranted. Serotonin has recently emerged as a growth factor for tumor cells, and its receptors may be potential therapeutic targets. The mechanism related to the behavior of the 5-HT7 receptor in NSCLC remains unknown.MethodsBoth gene expression analysis and immunohistochemical analysis were conducted to evaluate 5-HT7 receptor expression in NSCLC tissues. The correlation between 5-HT7 receptor expression and clinicopathological features was also examined. Cell proliferation was measured using a CCK8 (Cell Counting Kit-8) assay and colony formation, migration and invasion were evaluated by the Transwell assay. siRNA transfection and stimulation with the selective agonist LP211 were used to identify the involvement of molecules in proliferation, migration and invasion. Quantitative real-time chain reaction (qRT-PCR) and Western blotting were used to quantifiy mRNA and protein levels, respectively. Pathway inhibitors facilitated the exploration of possible signaling pathways regulated by the 5-HT7 receptor in migration and invasion.ResultsThe 5-HT7 receptor was overexpressed in NSCLC tumor tissues compared with adjacent normal lung tissues. High 5-HT7 receptor expression levels were correlated with lymph node metastasis (P=0.007) and advanced TNM stage (P=0.000) in NSCLC patients. The 5-HT7 receptor positively regulated cell proliferation, migration and invasion in NSCLC cells. The stimulatory effect of the 5-HT7 receptor on A549 cell migration and invasion may occur through the P38 pathway. In H1299 cells, the 5-HT7 receptor might positively regulate Src to promote cell migration and invasion.ConclusionOur findings suggest that the 5-HT7 receptor, which mediates NSCLC progression, may be a potential therapeutic target.

Vascular endothelial growth factor in tumor cells in platinum-containing chemotherapy of advanced ovarian cancer

Aim. Study of the relationship of vascular endothelial growth factor expression in tumor cells of ascites and primary tumor in patients with ascitic form of ovarian cancer undergoing neoadjuvant chemotherapy according to the AP scheme (doxorubicin + cisplatin).
 Methods. The level of vascular endothelial growth factor messenger ribonucleic acid (mRNA) was assessed using PCR-RT in epithelial cells of ascites and primary tumor tissue obtained intraoperatively after 2–4 courses of neoadjuvant chemotherapy according to the AP scheme from 25 patients with a verified diagnosis of ovarian cancer (serous adenocarcinoma) at stage III–IV according to the International Federation of Gynecology and Obstetrics. Processing of the results was performed using the software package Statistica 10.
 Results. An increase in the expression of vascular endothelial growth factor mRNA in epithelial cells of ascites in 60% of samples was established. In the intraoperatively obtained tumor tissue after 2–4 courses of neoadjuvant chemotherapy according to the AP scheme, vascular endothelial growth factor expression was increased in 73% of the samples. At the same time, the increase of relative expression in the tumor after neoadjuvant chemotherapy did not depend on the degree of therapeutic pathomorphosis but was related to early relapse and increased level of cancer antigen-125 (CA-125). Median of relapse-free survival in vascular endothelial growth factor-positive ovarian cancer was less than 5 months.
 Conclusion. Neoadjuvant chemotherapy according to the AP scheme increases the expression of vascular endothelial growth factor in the tumor tissue in advanced ovarian cancer; the degree of vascular endothelial growth factor overexpression in ovarian tumor is related to the presence of early relapse and an increase in the serum CA-125 level.

Abstract 5026: Tumor associated targeting with Manocept: HIV associated Kaposi's sarcoma as a model system

Abstract Introduction Inflammation appears to play a critical role in tumor development of HIV-associated Kaposi's sarcoma (KS). Specifically, emerging data show that KS tumor cells that co-express various macrophage (MO) antigens become resistant to current anti-viral therapies used to treat KS and AIDS. MOs also are a known source of KS tumor cell growth factors and substantial evidence suggests that tumor associated macrophages (TAMs) may represent a reservoir for HIV and its evolved retroviral variants. The MO pool driving these two pathological pathways share a common element rooted in the MOs, the CD206 human macrophage mannose receptor. Manocept, a molecular targeting agent, binds and enters MOs via pinocytosis of holo-CD206, providing a cell portal for the evaluation of Manocept as a MO and KS targeting agent. Methods Manocept was prepared as a synthetic molecule with a dextran backbone, and 12-20 mannose moieties. The reporter molecule (Cy3) was included as a fluorescent tracer for locating Manocept on and in MOs and KS tumor cells. Binding and localization Cy3-Manocept was assessed through intracellular visualization and flow cytometric quantitation of Cy3-Manocept binding and uptake using in vitro generation of monocyte-derived CD206+ MOs. The fresh HIV+ KS tumor tissue culture followed by immunofluorescence staining and confocal imaging was performed to confirm Cy3-Manocept uptake in KS tumor cells and TAMs. Results In vitro culture showed that Cy3-Manocept binds avidly to CD206 expressing MOs. Time course studies of increasing Cy3-Manocept concentrations confirmed continuous and ongoing uptake of Manocept into CD206+ MOs at 37°C. Fresh HIV+ KS tissue culture studies showed both Manocept uptake and CD206 staining of TAMs as well as KS tumor spindle cells (HHV8+ cells). Cy3-Manocept co-localized with CD206 in nearly all KS-associated cells expressing HHV8 and/or CD68 (Tissue MO marker), confirming that CD206 acts both as a target and Manocept concentrating receptor for TAMs and KS tumor cells. Conclusions Our results support the potential use of CD206 macrophage mannose receptor-targeted Manocept for imaging KS tumor cells, TAMs, and more importantly, for delivery of therapeutic/diagnostic agents capable of targeting all KS-associated cells including a potential MO reservoir for HIV. Citation Format: Rongzhen Zhang, Frederick O. Cope, Paige M. Bracci, Michael S. McGrath. Tumor associated targeting with Manocept: HIV associated Kaposi's sarcoma as a model system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5026. doi:10.1158/1538-7445.AM2015-5026

Sonodynamic therapy inhibits angiogenesis and tumor growth in a xenograft mouse model

Studies of sonodynamic therapy (SDT) have mainly focused on its direct cytotoxic effect on tumor cells. Its effects on the tumor microenvironment, especially angiogenesis, remain unknown. In this study, we found that SDT significantly inhibited endothelial cell proliferation, migration, invasion, and tube formation. Furthermore, in a tumor xenograft mouse model, SDT was found to remarkably suppress tumor growth, intratumoral vascularity, and expression of vascular endothelial growth factor in tumor cells. An ultrastructural study showed damage and disruption of tumor microvasculature after STD. Our results indicate that SDT inhibits neovascularization in tumor, which is partially responsible for the anti-tumor effect of SDT.

Pharmacokinetic study and effectiveness evaluation of slow-release PLGA-5-fluorouracil microsphere

The aim was to develop a slow-release poly-lactic-co-glycolic acid (PLGA)-5-fluorouracil microsphere, study the pharmacokinetic characteristics as well as to evaluate the effectiveness and safety of this preparation on colorectal tumor in vivo. The PLGA-5-fluorouracil microsphere was prepared based on a spray-drying method, and the drug loading of 5-fluorouracil (the percentage of 5-fluorouracil content in the whole microsphere), in vitro 5-fluorouracil release profile and pharmacokinetic characteristics were carried out through high-performance liquid chromatography. The inhibiting effect on tumor growth and safety was examined using in vivo subcutaneously (s.c.) inoculated colorectal tumor models of nude mice. The size of the microsphere was less than 100 μm, drug loading was 20 % and drug release time lasted as long as 30 days. Slow-release PLGA-5-fluorouracil microsphere had longer half-life time (t (1/2)), larger apparent volume of distribution (V ( d )) and smaller area under the curve (AUC) compared with 5-fluorouracil. PLGA-5-fluorouracil microsphere significantly restrained tumor growth and this effect correlated with decreased expression of vascular endothelial growth factor in tumor cells. Body weight measurement and blood analysis did not suggest significant adverse effects on the mice during the study. The slow-release PLGA-5-fluorouracil microsphere developed here was suitable for regional use; it has pharmacokinetic advantages and appears safe and effective in controlling the tumor growth. This preparation shows promise in reducing local recurrence of colorectal cancer after resection, but needs further investigation.

Inhibition of lung cancer cell proliferation mediated by human mesenchymal stem cells

Human mesenchymal stem cells (hMSCs) are mostly studied for their potential clinical use. Recently, much attention in the field of cancer research has been paid to hMSCs. In this study, we investigated the influence of hMSCs on the proliferation of lung cancer cell lines SK-MES-1 and A549 in vitro and in vivo by using a co-culture system and the hMSCs-conditioned medium. Our results demonstrated that hMSCs could inhibit the proliferation of SK-MES-1 and A549 cells, and induce the apoptosis of tumor cells in vitro via some soluble factors. Animal study showed that these soluble factors from hMSCs could suppress tumorigenesis and tumor angiogenesis by treating preliminarily tumor cells with the hMSCs-conditioned medium. The downregulated expression of vascular endothelial growth factor in tumor cells might be the mechanism of interference in tumor angiogenesis, which was verified by western blot analysis and immunohistochemistry assay. Taken together, our results suggested that the hMSCs could inhibit tumor cell growth by secreting some soluble factors.

VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer

Whereas the inhibition of vascular endothelial growth factor (VEGF) has shown promising results in sporadic colon cancer, the role of VEGF signaling in colitis-associated cancer (CAC) has not been addressed. We found that, unlike sporadic colorectal cancer and control patients, patients with CAC show activated VEGFR2 on intestinal epithelial cells (IECs). We then explored the function of VEGFR2 in a murine model of colitis-associated colon cancer characterized by increased VEGFR2 expression. Epithelial cells in tumor tissue expressed VEGFR2 and responded to VEGF stimulation with augmented VEGFR2-mediated proliferation. Blockade of VEGF function via soluble decoy receptors suppressed tumor development, inhibited tumor angiogenesis, and blocked tumor cell proliferation. Functional studies revealed that chronic inflammation leads to an up-regulation of VEGFR2 on IECs. Studies in conditional STAT3 mutant mice showed that VEGFR signaling requires STAT3 to promote epithelial cell proliferation and tumor growth in vivo. Thus, VEGFR-signaling acts as a direct growth factor for tumor cells in CAC, providing a molecular link between inflammation and the development of colon cancer.

Abstract 2467: Role of adrenomedullin in woodchuck hepatocarcinogenesis

Abstract The aim of this study is to investigate the role of adrenomedullin (AM) during the development of hepatocellular carcinoma (HCC). AM is a growth factor for tumor cells and induces angiogenesis. Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) represent the best animal model for studying hepadnavirus-induced HCC. We sought to determine whether AM signaling is functionally active in woodchuck HCC and how it correlates with tumor development and disease progression. Furthemore, increased expression and activity of matrix metalloproteinases (MMPs) in HCC patients is associated with advanced tumor stage, metastasis and poor survival. MMPs are further known to regulate AM cleavage. Therefore, we also sought to determine the role of MMPs in HCC development using the preclinical woodchuck model. For identifying a partial sequence of woodchuck AM (wAM), primers specific for human AM were utilized in PCR amplification. The resulting PCR products were sequenced and analyzed. The cellular localization of wAM was determined by immunohistochemical staining. AM and AKT expression levels were also compared by western blot between liver tissues from WHV-uninfected woodchucks, non-tumorous and tumorous liver tissues from chronic carrier woodchucks at different stages of HCC. Gelatin zymographic analysis was performed on woodchuck serum and liver samples in order to quantify the activity of MMPs following densitometry. The wAM consensus sequence revealed a 98% homology to human AM at the amino acid level. Compared to non-tumorous liver tissue, wAM protein expression was increased in adjacent tumorous tissues from the same chronic carrier woodchuck with HCC. wAM expression was detected mainly in hepatocytes and kupffer cells located within areas of portal hepatitis. In addition, the staining intensity for wAM was higher in tumorous hepatocytes than in non-tumorous or WHV-unifected hepatocytes. pAKT was also upregulated in tumoral liver tissues. Activity of MMP-9 was significantly increased in tumorous liver tissues as determined by zymography. Hepatic wAM gene expression in chronic carrier woodchucks is markedly upregulated during progression from normal to cancerous liver, and increases in wAM expression correlate with the degree of tumor malignancy in these animals. This increased wAM expression seems to be mediated through the activation of the PI3K (phosphoinositide 3-kinase)/Akt pathway. Furthermore, increased MMP-9 activity could be a factor in HCC invasiveness. Our results suggest that wAM-mediated neovascularization plays an important role in the hepatocarcinogenesis of WHV-infected woodchucks. Future studies will investigate if the blockage of the wAM signaling pathway in chronic carrier woodchucks alters hepadnavirus-induced liver carcinogenesis as a preclinical test for treatment of HCC in humans. This study was funded by a grant from the Spanish Ministry of Science and Innovation: SAF2009-13240-C02-01 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2467.

RhoC is essential for angiogenesis induced by hepatocellular carcinoma cells via regulation of endothelial cell organization

The angiogenesis induced by tumor cells is essential for metastasis of hepatocellular carcinoma. Available information suggests that RhoC participates in angiogenesis through regulation of vascular endothelial growth factor expression in tumor cells. For its broad functions in cell migration and cytoskeletal organization, we hypothesized that RhoC regulating angiogenesis does not exclusively depend on regulation of vascular endothelial growth factor expression. To address this question, in the present study, we used a retroviral small interfering RNA approach to selectively knockdown the expression of RhoC in a neovascularization model in vivo and in vitro. Our present results indicate that RhoC is the downstream regulator of vascular endothelial growth factor in endothelial cells and is essential for angiogenesis induced by vascular endothelial growth factor, notwithstanding that RhoC regulates the expression of vascular endothelial growth factor in tumor cells. Furthermore, we show that knockdown of RhoC is associated with the inhibition of invasion and migration but not apoptosis of endothelial cells. Knockdown of RhoC results in inhibition of endothelial cell organization through restraining the reorganization of F-actin filaments, which represses endothelial cell network and sprout formation. In conclusion, our results demonstrate that knockdown of RhoC inhibits angiogenesis induced by tumor cells not only through effecting the release of vascular endothelial growth factor, but also through inhibiting endothelial cell migration and organization, which implies that it blocks tumor metastasis by specifically inhibiting RhoC in endothelial cells.

Correlation between hypoxia-inducible factor and vascular endothelial growth factor expression under tumor neovascularization in hepatocellular carcinoma cell-implanted nude mice

Background: In a tumor, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) are induced to promote angiogenesis for the growth and metastasis of cells. There have been very few studies to examine in vivo relation between HIF-1α and VEGF during tumor progression. Objective: To study the relationship between HIF-1α and VEGF expressions under neovascularization induced by hepatocellular carcinoma cells (HepG2) implanted in nude mice. Methods: Male BALB/c-nude mice 8-10 weeks of age were used. A chamber was prepared on the dorsal skin in which HepG2 was transplanted to induce a tumor. On the day of the experiment, and on days 2, 7, and 14, microcirculation within the chamber was observed using fluorescence videomicroscopy. Based on the recorded video images, capillary vascularity (CV) was measured to examine tumor neovascularization. VEGF expression was measured in blood (serum) withdrawn, using enzyme immunoassay, while HIF-1α expression was measured on samples isolated from tumor tissue, using immunohistochemistry. Results: The measured CV significantly increased on day 7 and 14 compared to the aged-matched controls (p < 0.05). HIF-1α markedly expressed on day 2, and the expression declined on day 7 and 14 post-inoculation. VEGF expression in serum increased more on day 7 and 14 than on day 2. HIF-1α expression decreased with the increase in VEGF expression from 2 to 14 days after HepG2 implantation, showing a reverse correlation. Conclusion: HIF-1α expression existed prior to both VEGF expression and neovascularization in the tumor. An inhibitor of HIF-1α might be a therapeutic agent for reducing neovascularization via adaptation to hypoxia in tumors.

Poster 057: Metastasis-Associated MTA1 Expression in Oral Squamous Cell Carcinoma: Relationship With Lymph Node Metastasis

Metastasis-associated protein 1 (MTA1) is physiologically expressed at only lowlevels in human tissue, except testis. Its expression has been found to be associated with progression in solid cancers of various organs and cancer cell lines with high invasive potential and thus is believed to play a role in cancer progression to the metastatic state. Functional studies supported this by showing that experimental overexpression of MTA1 in keratinocytes is associated with increase in migration and invasion and survival in the anchorage-independent state. However, few reports have examined the role of MTA1 in oral squamous cell carcinoma. To determine the relationship between clinicopathologic factors and MTA1 expression in patients with oral squamous cell carcinoma, we investigated MTA1 gene expression and protein production. 38 oral squamous cell carcinomas (tongue carcinoma) were enrolled in this study. The expression of MTA1 was assayed immunohistochemically using polyclonal antibodies, and the expression of PCNA was assayed immunohistochemically using monoclonal antibody. The human oral squamous cell carcinoma cell lines, SAS, HSC-2, OSC19 and OSC20 were obtained from the Human Science Research Resource Bank. For PCR analysis, cDNA was amplified by Taq DNA polymerase. BioCoat Matrigel invasion chambers were used to assess cell invasion. Briefly, cells were seeded in the upper chamber. Cells on the reverse side of the insert were fixed and stained with DiffQuick. To investigate the correlation of MTA1 with cancer invasion, the effect of MTA1 inhibition was examined by RNA interference (RNAi). Significance was assessed by means of Student T test and Pearsons correlation coefficient. MTA1 protein expression was detected in 33 of 38 SCCs. There was no correlation between MTA1 expression and T category. There was correlation between MTA1 expression and N category and clinical stage. Immunohistochemical expression of MTA1 had no correlation with tumor cell growth factor (PCNA) and WHO histological malignancy grade. MTA1 protein production was strongly associated with cancer cell invasion (p<0.05), and there was significant correlation with lymph node metastasis and MTA1 protein production. HSC2 revealed low mRNA expression and OSC 20 revealed highest mRNA expression. In matrigel invasion assay, the HSC2 cell line revealed lowest invasion and the OSC20 cell line revealed highest invasion. RNAi-mediated MTA1 reduction decreased the invasion index (p<0.01). MTA1 may be a useful marker for lymph node metastasis, and MTA1 expression may be associated with increased invasive ability in oral squamous cell carcinomas.

Potential contribution of naïve immune effectors to oral tumor resistance: role in synergistic induction of VEGF, IL-6, and IL-8 secretion.

The aim of this study is to identify the phenotype of resistant oral tumors, and to delineate the contribution of immune effectors to resistance of oral tumors. UCLA-1 oral tumors which were resistant to NK cell mediated cytotoxicity secreted increased amounts of IL-6, IL-1beta, GM-CSF, and IL-8 when cultured with or without immune effectors. In addition, the levels of vascular endothelial growth factor (VEGF) secretion in the co-cultures of naïve immune effectors with UCLA-1 rose significantly when compared to tumor cells alone. IL-2 activated NK cells decreased VEGF secretion in all tumor cells. However, NK cells which were induced to undergo cell death with anti-CD16 antibody were not only unable to decrease VEGF secretion, but they also contributed further to the increase in VEGF secretion by oral tumors. Overall, we show in this paper that naïve as well as non-viable immune effectors may contribute to the growth and resistance of oral tumors by triggering the secretion of key tumor cell growth factors.

Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways

Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA. The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells. Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells. This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial growth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT signaling pathways.

An Immunohistochemical and Ultrastructural Study of Pancreatic Microcystic Serous Cyst Adenoma with Special Reference to Tumor-Associated Microvasculature and Vascular Endothelial Growth Factor in Tumor Cells

Pancreatic microcystic serous cyst adenomas are rare exocrine tumors composed of small cysts lined by glycogen-rich cells. The disease may be sporadic or present as part of von Hippel-Lindau (VHL) syndrome. Four sporadic cases of pancreatic serous cyst adenoma were examined by conventional histological, immunohistochemical, and ultrastructural methods. In the present study, new findings include the immunohistochemical identification of vascular endothelial growth factor (VEGF) and the lack of PDX-1 (putative master transcriptional factor in pancreatic stem cells) in the epithelial tumor cells. Ultrastructurally, many small blood vessels were intimately associated with epithelial tumor cells and adjacent fibroblastic cells. The observations suggest the possibility that VEGF-containing tumor cells act in a paracrine fashion to stimulate neovascularization; that peripheral blood in the vascular lumen might be filtered or processed by the endothelial and epithelial tumor cells; and that filtrates might therefore be stored as serous inclusions. It is hypothesized that pancreatic serous cyst adenomas might be under the abnormal regulation of the VHL gene, just like VHL disease itself and certain types of renal cell carcinoma, showing the distinctive histology of a rich vascularity intimately related to epithelial lining cells of cysts accompanied by stromal fibroblasts/myofibroblasts and collagenous stroma.

Increased Vascular Endothelial Growth Factor in Tumor Cells and Increased Production of the Receptor for Urokinase Plasminogen Activator in Endothelial Cells Are Associated with Lymph Node Metastasis in Human Breast Cancer

Increased Vascular Endothelial Growth Factor in Tumor Cells and Increased Production of the Receptor for Urokinase Plasminogen Activator in Endothelial Cells Are Associated with Lymph Node Metastasis in Human Breast Cancer

Increased Vascular Endothelial Growth Factor in Tumor Cells and Increased Production of the Receptor for Urokinase Plasminogen Activator in Endothelial Cells Are Associated with Lymph Node Metastasis in Human Breast Cancer

Increased Vascular Endothelial Growth Factor in Tumor Cells and Increased Production of the Receptor for Urokinase Plasminogen Activator in Endothelial Cells Are Associated with Lymph Node Metastasis in Human Breast Cancer

Interleukin 1 (IL-1)-dependent melanoma hepatic metastasis in vivo; increased endothelial adherence by IL-1-induced mannose receptors and growth factor production in vitro.

The growth of cancer cells in inflammatory tissue is often observed. This can be the result of favorable conditions for endothelial cell adherence and/or increased production of local growth factors. The role of the proinflammatory cytokine interleukin 1 (IL-1) in the prometastatic and growth-promoting environment of inflammation was studied in vivo, and the mechanism of cytokine action was studied in vitro as well. Systemic inflammation was induced by the intravenous injection of IL-1 beta or lipopolysaccharide (LPS), and the hepatic metastasizing ability of B16 melanoma (B16) cells following intrasplenic injection was studied. IL-1 receptor blockade was accomplished with the use of the IL-1 receptor antagonist (IL-1Ra). In vitro, IL-1Ra was used to assess the mechanism for prometastasis and growth promotion of cultured hepatic sinusoidal endothelium stimulated with LPS. There was a statistically significant (P < .01) enhancement in the parameters of hepatic metastasis when B16 cells were injected intrasplenically either 4 hours after IL-1 injection or 6 or 12 hours after LPS injection. IL-1Ra pretreatment reduced IL-1-induced enhancement of metastasis by 73%-87% and completely inhibited the augmentation of metastasis following LPS injection. In vitro, the adherence of melanoma cells to LPS-treated endothelium increased nearly twofold but was completely abrogated when IL-1Ra was added before LPS. Similar to melanoma adherence, a 2.5-fold increase (P < .05) in functional mannose receptors was observed with LPS treatment but was prevented by the addition of IL-1Ra did not affect basal mannose-receptor activity in unstimulated epithelium. Mannose-receptor activity and B16 cell adherence significantly correlated (r = .9) with LPS treatment. Conditioned medium from LPS-stimulated epithelium augmented B16 cell proliferation compared with control conditioned medium (P < .01). Production of B16 cell growth factor(s) was markedly reduced (P < .01) when IL-1Ra was added. These results demonstrate that systemic inflammation induces an enhancement of melanoma cell metastasis and growth by IL-1-dependent mechanisms in vivo. In vitro, the mechanism(s) is consistent with IL-1-mediated increase in expression of mannose receptors and production of tumor cell growth factor(s) from the endothelium. Given the multiple and complex cytokine cascade induced in vivo and in vitro during LPS-induced systemic inflammation, IL-1 plays a strategic role. Since IL-1Ra is without side effects in humans, studies on intraoperative infusion of IL-1Ra during tumor resection may be indicated.

Cytokine expression in large cell lymphoma associated with acquired immunodeficiency syndrome.

Cytokine expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) in a retrospective sampling of 16 AIDS-associated large cell lymphomas (LCL). IL-6 receptor (IL-6R) and IL-10 expression was detected in a majority of the tumor specimens tested, IL-6 expression was detected in 5 of 16 lymphomas that also expressed IL-6R, suggestive of an autocrine mechanism of disease. A subset of tumor samples described as mixed immunophenotype contained large numbers of infiltrating T lymphocytes and macrophages. Immunoperoxidase staining of a representative tumor of mixed immunophenotype demonstrated the presence of HIV-infected macrophages that also stained with anti-IL-6. This finding suggests that IL-6 produced by nonlymphoid cells may act as a paracrine growth factor for tumor cells that express IL-6R. Although earlier studies of AIDs burkitt's lymphoma cell lines suggested that IL-10 expression required EBV infection, 7 of 12 AIDS LCLs that expressed IL-10 did so in the absence of EBV by EBER in situ hybridization. Because AIDS LCLs frequently express cell surface CD5, we speculate that IL-10 may act as an autocrine or paracrine growth factor for this class of lymphoma. These studies suggest that IL-6 and IL-10 are involved in the pathogenesis of AIDS-associated large cell and mixed immunophenotype lymphoma.

Absence of Expression of c-sis and Transforming Growth Factor-β mRNA in Malignant Fibrous Histiocytoma

Total RNA was extracted from five malignant fibrous histiocytomas and two benign fibrohistiocytic lesions and assayed for mRNA expressions for transforming growth factor beta (TGF-β) and c-sis by Northern blot analysis. Production of both of these has been associated with cells of monocyte-macrophage lineage, and these factors have been shown to be important in physiologic mesenchymal cell proliferation. No mRNA expression of either TGF-β or c-sis was identified in any of the fibrohistiocytic tumor samples. The lack of expression of TGF-β and c-sis may be consistent with a nonhistiocytic origin of malignant fibrous histiocytoma, or may reflect transformation- associated loss of the normal molecular mechanisms of mesenchymal proliferation. The absence of c-sis mRNA expression can be reconciled with the prior immunohisto chemical demonstration of platelet-derived growth factor in tumor cells of malignant fibrous histiocytoma. Int J Surg Pathol(2):117-122, 1993