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Biomedical subjects

Lee M Ellis

Publications and source records attributed to Lee M Ellis.

104 records · Page 6Linked to original sources
PubMed2002

Antiangiogenic therapy targeting factors that enhance endothelial cell survival.

The process of angiogenesis involves the formation of new blood vessels from established vasculature and the maintenance of the fragile neovascular network. Recent studies have shown that several angiogenic factors not only induce angiogenesis but also act as endothelial cell (EC) survival factors. Vascular endothelial growth factor, a potent angiogenic factor, is also an EC survival factor via activation of EC-specific tyrosine kinase receptors. Angiopoietin-1 has recently been shown to stabilize EC networks by binding to the EC-specific tyrosine kinase receptor Tie-2; in contrast, angiopoietin-2 is antagonistic to angiopoietin-1 and destabilizes EC networks. Integrins may function as EC survival factors by preventing apoptosis by numerous mechanisms mediated by binding to the extracellular matrix. Integrins may also function in concert with vascular endothelial growth factor to promote EC survival. Lastly, pericytes contribute to EC stabilization by cell-cell contact and/or secretion of survival factors, such as vascular endothelial growth factor. Targeting EC survival factors may provide a novel antineoplastic strategy for cancer.

Angiogenesis Inhibitors↗
PubMed2002

Preoperative predictors of survival after resection of small hepatocellular carcinomas.

OBJECTIVE: To determine preoperative predictors of survival that can guide the choice of treatment for patients with small hepatocellular cancers (HCCs). SUMMARY BACKGROUND DATA: The treatment of patients with small (</=5 cm in diameter) HCCs is controversial. METHODS: A cohort of 249 patients (69 women, 180 men; median age 62 years) who underwent resection with curative intent for small HCC was identified from a multiinstitutional database. For each patient, the clinical data and pathology slides were reviewed. Six clinical factors (age, gender, preoperative alpha-fetoprotein level, hepatitis serology, number of tumors [single vs. multiple], and Child-Pugh score) and three pathologic factors (hepatitis activity score, fibrosis score, and Edmondson-Steiner tumor grade) that can be determined before surgery were correlated with survival. Log-rank tests and Cox proportional hazards modeling were used to determine factors influencing survival. RESULTS: The median overall survival for the entire cohort was 4.2 years. The estimated overall 5- and 8-year survival rates were 41.1% and 19.8%, respectively. Multivariate Cox analysis indicated that fibrosis score, Edmondson-Steiner grade, and Child-Pugh score were simultaneously significant predictors of survival after resection. A prognostic scoring system based on these covariates was derived and applied to the entire cohort. Patients lacking all three risk factors were assigned a score of 1, patients with one risk factor were assigned a score of 2, and patients with two or three risk factors were assigned a score of 3. Pairwise log-rank tests indicated significant differences in survival between scores 1 and 2, scores 2 and 3, and scores 1 and 3. This scoring system retained its prognostic significance when a subset of 98 patients with positive hepatitis C serology was analyzed separately. CONCLUSIONS: Patients with small HCCs who will derive the least benefit from resection can be identified before surgery using a score based on tumor grade and the severity of underlying liver disease. In these patients, transplantation and/or ablation should be considered as possible alternative therapies.

Carcinoma, Hepatocellular↗
PubMed2002

Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer.

Insulin-like growth factors and their principal receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF). The role of IGF-IR in regulating angiogenesis and metastases of human colon cancer has not been elucidated. To determine the in vitro and in vivo effects of IGF-IR in human colon cancer growth and angiogenesis, human KM12L4 colon cancer cells were transfected with a truncated dominant-negative form of IGF-IR (IGF-IR dom-neg). IGF-IR dom-neg-transfected cells demonstrated markedly decreased constitutive expression of VEGF mRNA and protein. Subcutaneous injections of IGF-IR dom-neg-transfected cells in nude mice led to significantly decreased tumor growth (p < 0.05) that was associated with decreased tumor cell proliferation, VEGF expression, and vessel count and with increased tumor cell apoptosis (p < 0.05 for all parameters compared with controls). In addition, pericyte coverage of endothelial cells was significantly decreased in tumors from IGF-IR dom-neg-transfected cells. Following this observation, we demonstrated in vitro that vascular smooth muscle cells migrated significantly less in conditioned medium derived from IGF-IR dom-neg-transfected cells compared with medium from control cells. After splenic injections, IGF-IR dom-neg transfectants failed to produce liver metastases, in contrast to parental cells and mock transfectants (p < 0.05). In addition, IGF-IR dom-neg-transfected cells failed to form liver tumors after direct injection into the liver. These studies demonstrate that the IGF-IR plays an important role in multiple mechanisms that mediate the growth, angiogenesis, and metastasis of human colon cancer. IGF-IR is a valid target for the therapy of human colon cancer.

Cell Division↗
PubMed2002

Multiparametric in situ mRNA hybridization analysis of gastric biopsies predicts lymph node metastasis in patients with gastric carcinoma.

We examined the expression level of several genes that regulate different steps in metastasis formation in formalin-fixed, paraffin-embedded biopsies of 189 primary human gastric carcinomas prior to surgical resection in patients in whom lymph node metastasis was not evident by endoscopic ultrasound or computed tomography (CT) scan. The expressions of epidermal growth factor receptor (EGF-R), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and E-cadherin were examined by a colorimetric in situ mRNA hybridization technique. The integrity of the mRNAs was verified, leaving 161 (85.2%) patients for study. After gastrectomy, 82 patients had positive lymph nodes and 79 patients had negative lymph nodes. The concurrent expression levels of MMP-2 and E-cadherin mRNAs were significantly higher and lower, respectively, in the metastatic tumors than the non-metastatic tumors. Expression of EGF-R and VEGF was not different between the metastatic and non-metastatic tumors. However, when only the intestinal-type of gastric cancer was evaluated, the level of VEGF mRNA was significantly higher in tumors associated with lymph node metastasis than in those without metastasis. However, a high MMP-2:E-cadherin ratio significantly correlated with lymph node metastasis in both types of gastric cancer. These results suggest that multiparametric in situ hybridization analysis for several metastasis-related genes may allow the preoperative prediction of lymph node metastasis from gastric cancer.

Adult↗
PubMed2002

Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts.

Colon carcinomas frequently express the epidermal growth factor receptor (EGFR), and this expression correlates with more aggressive disease and poor prognosis. Previous studies have shown that EGFR blockade by monoclonal antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these tumors in athymic mice. In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice. IMC-C225 was tested at a dose of 1 or 0.5 mg administered q3d. CPT-11 was administered at a dose of 100 mg/kg/week or a maximum tolerated dose of 150 mg/kg/week. Treatment with the combination of IMC-C225 (1 and 0.5 mg) and CPT-11 (100 mg/kg) significantly inhibited the growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (P < 0.05). Combination therapy with IMC-C225 (1 mg) and the MTD of CPT-11 (150 mg/kg) resulted in a regression rate of 100 and 60% of established DLD-1 and HT-29 tumors, respectively. In a refractory tumor model, combined treatment with IMC-C225 and CPT-11 significantly inhibited the growth of CPT-11 refractory DLD-1 and HT-29 tumors, whereas either agent alone did not control tumor growth. Histological examination of treated tumors showed extensive tumor necrosis, decreased tumor cell proliferation, increased tumor cell apoptosis, and a marked decrease in tumor vasculature. These results suggest that EGFR blockade by IMC-C225 combined with topoisomerase I inhibitors may be an effective therapy against chemorefractory colorectal carcinoma tumors.

Animals↗
PubMed2002

Angiopoietins and their role in colon cancer angiogenesis.

Tumor angiogenesis is a complicated process that is regulated by numerous factors simultaneously and in a coordinated fashion. Angiogenic factors drive the process of neovascularization, but the initiation of angiogenesis involves priming of endothelial cells so that they will respond to mitogenic stimuli. The angiopoietins (Ang) -1 and -2 mediate endothelial cell stability through binding to their endothelial cell-specific receptor, Tie-2. Ang-1 leads to endothelial cell stability, and, in vivo, to an actual decrease in angiogenesis. This is likely due to its ability to enhance adhesion to the perivascular tissues. In contrast, Ang-2 leads to endothelial cell instability and may be an initiating factor in angiogenesis, priming endothelial cells for mitogenic signals. Thus, a novel antiangiogenic strategy may be one that leads to enhanced endothelial cell stability, thereby protecting endothelial cells from standard angiogenic stimuli. This may ultimately lead to tumor dormancy by transforming a rapidly growing tumor into an indolent tumor.

Angiopoietin-1↗
PubMed2002

Synopsis of angiogenesis inhibitors in oncology.

Angiogenesis is a dynamic process essential for primary tumor growth and metastases. New insights into the basic understanding of the biologic processes responsible for angiogenesis have led to the characterization of potential therapeutic targets. Several strategies for the development of antiangiogenic therapeutic modalities have been employed, including agents that (1) decrease the activity of specific angiogenic factors, (2) decrease th$ activity of endothelial survival factors, (3) increase the activity of naturally occurring antiangiogenic agents, or (4) indirectly downregulate angiogenic and survivalfactor activity. Because antiangiogenic therapy is unlikely to induce tumor regression, the criteria for efficacy must be evaluated by means other than the standard response criteria used to evaluate cytotoxic chemotherapy. Further, the redundancy of molecules responsible for the angiogenic process suggests it is unlikely that a single antiangiogenic agent will provide prolonged inhibition of angiogenesis. Nevertheless, the understanding of the basic principles that drive tumor angiogenesis will lead to the development of therapies that will likely prolong survival without the toxicity associated with standard chemotherapy.

Angiogenesis Inhibitors↗
PubMed2002

Blockade of insulin-like growth factor I receptor function inhibits growth and angiogenesis of colon cancer.

PURPOSE AND EXPERIMENTAL DESIGN: Insulin-like growth factors (IGFs) I and II and their principle receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF). To elucidate the in vitro and in vivo effects of IGF-IR in human colon cancer growth and angiogenesis, HT29 cells were transfected with a truncated dominant-negative (DN) form of IGF-IR or vector alone. RESULTS: IGF-I increased VEGF expression in parental and vector-transfected cells, whereas IGF-I induction of VEGF mRNA and protein was abrogated in IGF-IR DN cells. The IGF-IR DN cells demonstrated inhibited growth in both monolayer culture and soft agar (P < 0.05). s.c. injections of IGF-IR DN cells in nude mice led to significantly decreased tumor growth (P < 0.05). Immunohistochemical analyses revealed that IGF-I DN tumors demonstrated decreased tumor cell proliferation, VEGF expression, and vessel count and increased tumor cell apoptosis (P < 0.05 for all parameters compared with controls). Furthermore, IGF-IR DN-transfected cells yielded significantly decreased tumorigenicity and growth in the liver. CONCLUSIONS: These studies demonstrate that the IGF ligand-receptor system plays an important role in multiple mechanisms that mediate human colon cancer growth including regulation of VEGF and angiogenesis.

Animals↗
PubMedDate not supplied

Predictors of microvascular invasion in patients with hepatocellular carcinoma who are candidates for orthotopic liver transplantation.

Microvascular invasion affects survival after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). We sought to identify preoperative predictors of microvascular invasion in patients with HCC who were candidates for OLT. A cohort of 245 patients who underwent resection for HCC and fulfilled the criteria for OLT (i.e., single tumors < or =5 cm or no more than three tumors < or =3 cm) were identified from a multi-institutional database. Thirty-three percent of the patients had pathologic evidence of microvascular invasion. Thirty percent of patients with single tumors and 47% with multiple tumors had microvascular invasion (P = 0.04). Only 25% of patients with tumors smaller than < or =2 cm had microvascular invasion, compared to 31% and 50% with tumors greater than 2 to 4 cm or larger than 4 cm, respectively (P = 0.01). Tumor grade was highly correlated with microvascular invasion: 12% of patients with well-differentiated tumors had microvascular invasion, compared to 29% and 50% with moderately or poorly differentiated tumors, respectively (P < 0.001). The independent predictors of microvascular invasion were tumor size greater than 4 cm (odds ratio [OR], 3.0, 95% confidence interval [CI ], 1.2 to 7.1), and high tumor grade (OR, 6.3; 95% CI, 2.0 to 19.9). Tumor size and grade are strong predictors of microvascular invasion. A tumor biopsy with pathologic grading at the time of pretransplantation ablative therapy could improve selection of patients with HCC for OLT.

Adult↗
PubMedDate not supplied

Increased apoptosis in metastatic human colonic adenocarcinomas.

Recent work suggests that apoptosis is disrupted during the progression of many solid tumors. Isogenic metastatic colon adenocarcinoma cells displayed significantly higher levels of staurosporine-induced apoptosis compared to their nonmetastatic counterparts in vitro. In addition, analysis of 15 matched primary tumors and liver metastases demonstrated that the levels of apoptosis were significantly higher in the metastases, and this increased cell death was associated with significantly lower levels of Bcl-2 protein expression. Our data demonstrate that the molecular events associated with acquisition of the metastatic phenotype sensitize colon cancer cells to some pro-apoptotic stimuli.

Adenocarcinoma↗
PubMedDate not supplied

The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion.

We previously reported that vessel count, vascular endothelial growth factor (VEGF) and platelet derived endothelial cell growth factor (PD-ECGF) expression are associated with metastasis formation in human colon cancer. This study was done to determine a stage of colon cancer progression where induction of these factors occurred (i.e. the angiogenic switch). We examined vessel count, VEGF, and matrix metalloproteinase (MMP)-7 expression in cancer cells and PD-ECGF expression in infiltrating cells in 25 adenomas, 35 mucosal cancers (Tis), 29 submucosal invasive cancers (T1) and 33 muscularis propria invasive cancers (T2) by immunostaining. The intensity of staining of VEGF and MMP-7 was evaluated blindly at the invasive edge and was confirmed by image analysis. Intensity of staining for these factors was graded on a scale of 0 to 3+, with 0 representing no detectable stain and 3+ representing the strongest stain. Intensites of PD-ECGF-positive infiltrating cells were similar on a scale 0 to 3+, as previous studies from our laboratory have demonstrated that PD-ECGF is expressed primarily in tumor infiltrating cells. The vessel density was 12.7+/-2.2 (SE) in adenoma, 11.8+/-1.7 in Tis, 35.0+/-6.5 in T1, and 35.2+/-5.3 in T2. There were significant differences in vessel densities between Tis and T1 (p<0.001). The intensities of VEGF expression were 0.6+/-0.1, 0.9+/-0.2, 1.7+/-0.3, and 1.8+/-0.3 for adenoma, Tis, T1 and T2, respectively, with significant differences between in Tis and T1 (p<0.001). There were also significant differences in the intensities of the expression of MMP-7 and PD-ECGF between Tis and T1. These results suggest that angiogenic switch may occur between Tis and T1, i.e. simultaneous to initiation of invasion, in the early development of colon cancer.

Adenoma↗
PubMedDate not supplied

Induction of apoptosis by the green tea flavonol (-)-epigallocatechin-3-gallate in human endothelial ECV 304 cells.

We have previously shown that treatment with (-)-epigallocatechin-3-gallate (EGCG) inhibited vascularity and tumor growth in human colon cancer xenografts in nude mice (Jung et al: Br J Cancer 84, 2001). In this study, we examined whether endothelial cell death by EGCG is mediated by apoptosis and which molecular mechanisms are involved in this process. EGCG was found to suppress cell growth and induce apoptosis largely through mitochondrial depolarization, activation of caspase-3 and cleavage of DNA fragmentation factor-45 in human endothelial ECV 304 cells. The induction of apoptosis by EGCG was confirmed by cleaved and condensed nuclear chromatin and DNA hypoploidy. These results suggest that EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through inducing endothelial apoptosis.

Angiogenesis Inhibitors↗