Biomedical subjects

Lee M Ellis

Publications and source records attributed to Lee M Ellis.

At least 19 recordsLinked to original sources

PubMed2007

Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model.

The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1alpha (HIF-1alpha). Since mTOR is an upstream regulator of HIF-1alpha, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1alpha activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1alpha activation, and significantly impaired tumor cell migration. In vivo, rapamycin-treatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy.

Adenocarcinoma↗

PubMed2006

Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells.

The guanine nucleotide exchange factor Tiam1 regulates numerous biologic properties including migration and invasion. We demonstrated previously that colon tumor cells biologically selected for increased migration were increased in Tiam1 expression. Cells selected for increased Tiam1 expression or that ectopically overexpress Tiam1 were increased in metastatic potential. Here, we demonstrate that Tiam1 regulates additional functions associated with metastasis, including reduced cellular adhesion and resistance to anoikis. Tiam1 effects on cellular migration are mediated through its downstream substrate, Rac. Increased Tiam1 expression also leads to anoikis-resistance, whereas decreasing Tiam1 expression by siRNA sensitizes cells to this form of apoptosis; however, Tiam1's regulation of anoikis is Rac-independent. Staurosporine sensitivity is also Rac-independent, suggesting Tiam1's effects on apoptosis require other effectors. As many of the observed phenotypes are characteristic of a transition of transformed epithelial cells to a mesenchymal-like phenotype, we also examined biochemical properties associated with an EMT. We demonstrate an increase in vimentin expression in cell lines that overexpress Tiam1 and have a more metastatic phenotype. Concomitant with this increase, we observe a decrease in E-cadherin expression in these cells. Lastly, we stained a panel of human colorectal specimens and adjacent normal tissue, and demonstrate that Tiam1 is overexpressed in a subset of human colorectal tumors. In summary, in colon tumor cells, Tiam1 affects multiple properties associated with acquisition of the metastatic phenotype, and may represent a marker of colon tumor progression and metastasis in a subset of tumors.

Adenocarcinoma↗

PubMed2006

Production of VEGF165 by Ewing's sarcoma cells induces vasculogenesis and the incorporation of CD34+ stem cells into the expanding tumor vasculature.

The Ewing's sarcoma cell line TC71 overexpresses vascular endothelial growth factor isoform 165 (VEGF165), a potent proangiogenic molecule that induces endothelial cell proliferation, migration, and chemotaxis. CD34+ bone marrow stem cells can differentiate into endothelial and hematopoietic cells. We used a transplant model to determine whether CD34+ cells migrate from the bone marrow to Ewing's sarcoma tumors and participate in the neovascularization process that supports tumor growth. We also examined the role of VEGF165 in CD34+ cell migration. Human umbilical cord CD34+ cells were transplanted into sublethally irradiated severe combined immunodeficient mice. Seven days later, the mice were injected subcutaneously with TC71 tumor cells. Tumors were excised 2 weeks later and analyzed by immunohistochemistry. The tumor sections expressed both human VE-cadherin and mouse CD31, indicating involvement of donor-derived human cells in the tumor vessels. To determine the role of VEGF165 in the chemoattraction of CD34+ cells, we generated two VEGF165-deficient TC71 clones, a stable anti-sense VEGF165 cell line (Clone 17) and a VEGF165 siRNA-inhibited clone (TC/siVEGF(7-1)). The resulting VEGF165-deficient tumor cells had normal growth rates in vitro, but had delayed growth when implanted into mice. Immunohistochemical analysis revealed decreased infiltration of CD34+ cells into both VEGF165-deficient tumors. These data show that bone marrow stem cells contribute to the growing tumor vasculature in Ewing's sarcoma and that VEGF165 is critical for the migration of CD34+ cells from the bone marrow into the tumor.

Animals↗

PubMed2006

Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines.

PURPOSE: Epithelial-to-mesenchymal transition (EMT) is a process whereby cells acquire molecular alterations that facilitate cell motility and invasion. In preliminary studies, we observed that oxaliplatin-resistant (OxR) colorectal cancer (CRC) cells underwent morphologic changes suggestive of a migratory phenotype, leading us to hypothesize that OxR CRC cells undergo EMT. EXPERIMENTAL DESIGN: The human CRC cell lines KM12L4 and HT29 were exposed to increasing doses of oxaliplatin to establish stable cell lines resistant to oxaliplatin. Migration and invasion were assessed by modified Boyden chamber assays. Morphologic and molecular changes characteristic of EMT were determined by immunofluorescence staining and Western blot analyses. RESULTS: The OxR cells showed phenotypic changes consistent with EMT: spindle-cell shape, loss of polarity, intercellular separation, and pseudopodia formation. KM12L4 and HT29 OxR cells exhibited an approximately 8- to 15-fold increase in migrating and invading cells, respectively (P < 0.005 for both). Immunofluorescence staining of OxR cells revealed translocation of E-cadherin and beta-catenin from their usual membrane-bound complex to the cytoplasm and nucleus, respectively. The OxR cells also had decreased expression of the epithelial adhesion molecules E-cadherin and plakoglobin and an increase in the mesenchymal marker vimentin. The KM12L4 OxR cells exhibited increased nuclear expression of Snail, an EMT-regulatory transcription factor, whereas the HT29 OxR cells exhibited an increase in nuclear expression of the EMT-associated transcription factor nuclear factor kappaB. CONCLUSION: We hypothesize that induction of EMT may contribute to the decreased efficacy of therapy in chemoresistant CRC, as the tumor cells switch from a proliferative to invasive phenotype. Further understanding of the mechanisms of chemoresistance in CRC will enable improvements in chemotherapy for metastatic disease.

Antineoplastic Agents↗

PubMed2006

Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in vivo model of pancreatic cancer.

PURPOSE: Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another's expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts. EXPERIMENTAL DESIGN: L3.6pl human pancreatic cancer cells were s.c. implanted in nude mice. On day 6, mice were randomized to receive (a) PBS (control), (b) DC101 [VEGF receptor 2 (VEGFR-2) antibody] by i.p. injection, (c) N-nitro-l-arginine (NNLA; NOS inhibitor) in the drinking water, or (d) both DC101 and NNLA. Mice were killed on day 20. RESULTS: DC101 and NNLA as single agents inhibited tumor growth by approximately 50% to 60% (P < 0.008 for both). Furthermore, combined therapy inhibited mean tumor growth by 89% (P < 0.008). Combined inhibition of VEGFR-2 and NOS also decreased mean vessel counts by 65% (P < 0.03) and vessel area by 80% versus controls (P < 0.001). In contrast to DC101 where vessel diameter was similar to control, NNLA decreased mean vessel diameter by 42% (P < 0.001). NNLA also led to a 54% (P < 0.03) decrease in tumor uptake of the perfusion marker Hoechst 33342 versus controls whereas DC101 decreased Hoechst 33342 staining by 43% (P < 0.03). The combination of inhibitors decreased perfusion by 73% (P < 0.03). CONCLUSIONS: Although VEGFR-2 can mediate NOS activity, the combination of VEGFR-2 and NOS inhibition significantly increased the antivascular effect over single agent therapy. The addition of NOS inhibition led to an even further alteration of tumor vessel morphology and vascular perfusion compared with VEGFR-2 blockade, suggesting that NO and VEGFR-2 have distinct but complementary effects on the tumor vasculature.

Animals↗

PubMed2006

Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer.

PURPOSE: To study the safety of bevacizumab with capecitabine-based chemoradiotherapy. PATIENTS AND METHODS: Patients with inoperable pancreatic adenocarcinoma received bevacizumab 2 weeks before radiotherapy (50.4 Gy treating the primary tumor and gross adenopathy), every 2 weeks during radiotherapy (12 patients each at 2.5, 5.0, 7.5, and 10 mg/kg), and after radiotherapy until disease progression. Capecitabine was administered on days 14 through 52 (650 mg/m2 orally twice daily for the first six patients; 825 mg/m2 for the remaining patients). RESULTS: Significant acute gastrointestinal (43% grade 2; 4% grade 3), hand and foot syndrome (21% grade 2), and transient hematologic (8% grade 3 or greater) events were uncommon with protocol mandated dose reductions of capecitabine grade 2 toxicity (43% of patients). Among the first 30 patients treated, three patients had tumor-associated bleeding duodenal ulcers, and one had a contained duodenal perforation. No additional bleeding events occurred among the final 18 patients after patients with duodenal involvement by tumor were excluded. Nine (20%) of 46 assessable patients had confirmed partial responses until distant progression for a median of 6.2 months. Four patients have undergone pancreaticoduodenectomy without perioperative complication. The median survival was 11.6 months (95% CI, 9.6 to 13.6), from the start of protocol therapy. CONCLUSION: Concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen. However, ulceration and bleeding in the radiation field possibly related to bevacizumab occurred when tumor involved the duodenal mucosa. The encouraging efficacy end points suggest that the further study of bevacizumab with chemoradiotherapy is warranted.

Adult↗

PubMed2006

Accuracy of preoperative imaging of hepatic tumors with helical computed tomography.

BACKGROUND: The accuracy of preoperative computed tomography (CT) scans in the era of modern imaging techniques with helical, high-resolution CT has not been adequately assessed. We reviewed the data from our departmental prospective database with the hypothesis that intraoperative ultrasonography (IOUS) still detects more hepatic tumors than are evident on preoperative helical CT scans. METHODS: All patients who underwent surgical resection and/or radiofrequency ablation of primary or metastatic hepatic tumors between January 2001 and July 2002 were included in the review. All patients had preoperative helical CT imaging followed by hepatic IOUS. The number of malignant lesions and evidence of local disease identified by the preoperative CT scan versus IOUS and surgical exploration were compared. RESULTS: In this time period, 250 patients underwent surgical resection and/or radiofrequency ablation of hepatic tumors. In 67 (27%) of these patients, IOUS identified more hepatic tumors than were seen on preoperative helical CT scan. In eight patients (3%), CT underestimated local extension of the disease into the diaphragm. The incidence of inaccurate preoperative prediction of the extent of disease increased significantly with a greater number of hepatic tumors. CONCLUSIONS: IOUS identified additional hepatic tumors in 27% of patients who underwent hepatic resection after state-of-the-art preoperative CT imaging. This study provides evidence that IOUS remains an essential part of the complete assessment of hepatic malignancies in patients who receive surgical treatment.

Humans↗

PubMed2006

Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells.

Our laboratory has shown that vascular endothelial growth factor receptor-1 (VEGFR-1) expression on human pancreatic cancer cell lines mediates cell migration and invasion. Because epithelial to mesenchymal transition (EMT) also plays a role in cell motility by altering the cell phenotype and morphology, we hypothesized that VEGFR-1 activation induces molecular alterations that mediate EMT. Our treatment of the human pancreatic cancer cell line L3.6pl with the VEGFR-1 ligands VEGF-A and VEGF-B led to morphologic changes characteristic of EMT, including loss of polarity, increased intercellular separation, and the presence of pseudopodia. Immunofluorescent staining with antibodies to E-cadherin and beta-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and beta-catenin from their usual cell membrane-bound location to the cytoplasm and nucleus, respectively. Western blotting showed that VEGFR-1 activation led to decreased expression of the epithelial markers E-cadherin and plakoglobin, increased expression of the mesenchymal markers vimentin and N-cadherin, and increased nuclear expression of beta-catenin. Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced immunohistochemical and molecular changes in E-cadherin. VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug. The changes mediated by VEGFR-1 in this pancreatic carcinoma cell line are highly consistent with the changes characteristic of EMT. Given our previous finding of VEGFR-1-mediated tumor cell invasion and migration in pancreatic carcinoma cells, we hypothesize that VEGFR-1 plays a role in tumor progression in pancreatic cancer through the induction of EMT.

Cell Line, Tumor↗

PubMed2006

Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver.

HYPOTHESIS: A subset of patients with sarcoma liver metastasis may benefit from hepatic resection and/or ablation. DESIGN: Retrospective review of prospectively collected cancer center database records. PATIENTS AND METHODS: Sixty-six patients who underwent hepatic resection and/or open radiofrequency ablation of metastatic sarcoma between July 1, 1996, and April 30, 2005, were identified from the database. Clinicopathologic, operative, recurrence, and long-term survival data were analyzed. RESULTS: The primary sarcoma site was the abdomen or retroperitoneum (n = 22), stomach (n = 18), small or large bowel (n = 17), pelvis (n = 4), uterus (n = 3), or other (n = 2). Tumor pathologic types included gastrointestinal stromal tumor (n = 36), leiomyosarcoma (n = 18), and sarcoma not otherwise classified (n = 12). Thirty-five patients underwent resection, 18 underwent resection plus radiofrequency ablation, and 13 underwent radiofrequency ablation only. With a median follow-up of 35.8 months, 44 patients (66.7%) had recurrence (intrahepatic only, n = 16; extrahepatic only, n = 11; both, n = 17). Treatment with radiofrequency ablation (either alone or combined with resection) (P = .002) and lack of adjuvant chemotherapy (P = .01) predicted shorter disease-free survival. The 1-, 3-, and 5-year overall survival rates were 91.2%, 65.4%, and 27.1%, respectively. Patients with gastrointestinal stromal tumor who were treated with adjuvant imatinib mesylate had the longest median survival (not reached) (P = .003). CONCLUSIONS: Long-term survival can be achieved following surgical treatment of sarcoma liver metastasis, especially in patients with gastrointestinal stromal tumor. Patients with sarcoma liver metastasis should be evaluated by a multidisciplinary team, as recurrence is common and adjuvant therapy may prolong survival.

Adult↗

PubMed2006

Intracellular signaling in tumor and endothelial cells: The expected and, yet again, the unexpected.

In this issue of Cancer Cell, Phung and coworkers demonstrate that sustained endothelial activation of Akt by expression of constitutively activated Akt1 (myrAkt1) leads to blood vessels that essentially recapitulate the complex structural and functional abnormalities of tumor vessels. The authors provide evidence that rapamycin inhibition of PI3K/Akt/mTOR signaling in endothelial cells (ECs), by either reducing Akt activity or blocking mTOR, reverses the pathologic effects associated with excess VEGF signaling in the tumor vasculature. However, unexpected findings following mTOR inhibition in vivo highlight the seemingly paradoxical and complex effects of rapamycin on various cell types within the tumor microenvironment.

Antibiotics, Antineoplastic↗

PubMed2006

Debunking dogma: surgery for four or more colorectal liver metastases is justified.

Treatment of four or more colorectal liver metastases (CRLMs) is controversial and remains a relative contraindication to surgery at some institutions. We sought to assess the outcome of patients with four or more CRLMs treated with surgery. Patients (159) with four or more CRLMs were treated surgically at a single institution. The median number of treated lesions was 5 (range, 4-14). The majority of patients received neoadjuvant chemotherapy (89.9%). Forty-six (29.0%) patients underwent resection only, 12 (7.5%) underwent radiofrequency ablation (RFA) only, and 101 (63.5%) underwent resection plus RFA. The 5-year actuarial disease-free and overall survival rates were 21.5% and 50.9%, respectively. Patients who underwent RFA as part of their surgical procedure (hazard ratio [HR] = 1.81, P = 0.03) and those with a positive surgical resection margin (HR = 1.52, P = 0.01) were more likely to have a shorter time to recurrence. Patients who did not have a reduction in tumor size following neoadjuvant chemotherapy had a higher likelihood of death following surgical treatment (HR = 2.53, P = 0.01). Patients with four or more CRLMs should be considered for aggressive surgical treatment, including liver resection with or without RFA, in order to improve the chance of long-term survival. Certain clinicopathologic factors, including lack of response to neoadjuvant chemotherapy, were associated with a worse prognosis.

Adult↗

PubMed2006

Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer.

Tumor angiogenesis is a complex process that requires the coordinated activities of various effector molecules and cell types. While tumor vasculature can nourish the tumor, it is structurally and functionally abnormal, leading to elevated interstitial pressure and non-uniform tumor perfusion. The resultant hypoxia leads to the selection of more aggressive tumor cells, owing in part to an increase in the levels of the transcription factor hypoxia-inducible factor-1, which in turn leads to an increase in the expression of vascular endothelial growth factor (VEGF). The expression of VEGF is upregulated in many tumors, and the levels of this factor correlate not only with the extent of tumor angiogenesis but also with clinical prognosis. VEGF-targeted therapies, such as bevacizumab, exert their effects through a number of potential mechanisms, including (1) inhibition of new vessel growth, (2) regression of newly formed tumor vasculature, (3) alteration of vascular function and tumor blood flow ("normalization"), and (4) direct effects on tumor cells. Because of the presumed cytostatic mechanism of action of antiangiogenic agents, the efficacy of bevacizumab is most appropriately assessed through survival end points rather than the objective-response end points that have traditionally been used with cytotoxic agents. However, bevacizumab has been shown to increase the response rates with chemotherapy in almost all tumor types studied in phase III trials.

Angiogenesis Inhibitors↗

PubMed2006

Clinical and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer.

OBJECTIVES: To identify predictive factors for locoregional recurrence (LR), distant metastasis (DM), and overall survival (OS) in patients treated with chemoradiation and surgery for rectal cancer. METHODS: Between 1989 and 2001, 470 patients with rectal cancer were treated with preoperative (89%) or postoperative (11%) chemoradiation and mesorectal excision. Median radiation dose was 45 Gy; 97% received concurrent infusional 5-fluorouracil, and 65% received adjuvant chemotherapy. Median follow-up interval was 5.7 years. RESULTS: The 5-year rates of freedom from LR, freedom from DM, and OS were 90%, 79%, and 80%, respectively. On univariate analysis, significant predictors of LR were female sex, clinical T stage, pathologic T and N stages, and positive radial margin. Significant univariate predictors of DM were circumferential extent of tumor, tumor immobility, lymphovascular invasion, perineural involvement, and pathologic T and N stages. Significant univariate predictors of lower OS were age, circumferential extent of tumor, shorter distance from anal verge, tumor size, tumor immobility, anal canal involvement, lymphovascular invasion, perineural involvement, positive radial margin, and pathologic T and N stages. On Cox multivariate analysis, female sex and pathologic T and N stages independently predicted for LR; pathologic T and N stages independently predicted for DM; and age, circumferential extent of tumor, positive radial margin, and pathologic T and N stages independently predicted for lower OS. CONCLUSIONS: Pathologic T and N stages significantly predicted for all 3 end points (LR, DM and OS) on multivariate analysis. Investigations of more aggressive adjuvant chemotherapy appear warranted for pathologic stage T3/T4 or N1/2 rectal cancer.

Adult↗

PubMed2006

Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells.

Pancreatic carcinoma cells overexpress the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) and the hepatocyte growth factor (HGF) receptor, c-Met, which are both known to mediate tumor cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion of human pancreatic carcinoma cells and that IGF-I-mediated migration and invasion depend on c-Met. Migration and invasion assays were done with the human pancreatic cancer cell line L3.6pl treated with PBS, IGF-I, HGF, or IGF-I plus HGF. To determine if c-Met is necessary for IGF-IR-mediated migration and invasion, c-Met was down-regulated in L3.6pl cells via adenoviral infection with a c-Met ribozyme before IGF-I treatment. IGF-I and HGF increased cell migration and invasion. Furthermore, IGF-I plus HGF had a greater than additive effect on cell migration and invasion compared with either growth factor alone. Down-regulation of c-Met nearly completely inhibited IGF-I-mediated migration and invasion. Our findings suggest that IGF-IR and c-Met cooperate to induce migration and invasion of human pancreatic carcinoma cells. Furthermore, c-Met is required for both HGF- and IGF-I-mediated migration and invasion. Elucidation of the signaling pathways that contribute to tumor progression and metastasis should provide a foundation for the development of targeted therapies for pancreatic carcinoma.

Carcinoma↗

PubMed2006

The role of neuropilins in cancer.

Neuropilins are multifunctional non-tyrosine kinase receptors that bind to class 3 semaphorins and vascular endothelial growth factor. NRP-1 and NRP-2 were first identified for their key role in mediating axonal guidance in the developing nervous system through their interactions with class 3 semaphorins. Growing evidence supports a critical role for these receptors in tumor progression. Neuropilin expression is up-regulated in multiple tumor types, and correlates with tumor progression and prognosis in specific tumors. Neuropilins may indirectly mediate effects on tumor progression by affecting angiogenesis or directly through effects on tumor cells. This article reviews emerging evidence for the role of neuropilins in tumor biology. The therapeutic implications of these data are far-reaching and suggest that neuropilin-targeted interventions may be useful as a component of antineoplastic therapy.

Animals↗

PubMed2006

The role of nitric oxide in mediating tumour blood flow.

Nitric oxide (NO) is a ubiquitous molecule with a myriad of physiological and pathophysiological roles. It has numerous direct and indirect effects on tumour vasculature as both a regulatory and effector molecule. NO affects tumour blood flow through its effects on tumour angiogenesis, vascular tone and vascular permeability, partly via its interaction with vascular endothelial growth factor. In this review, the authors examine the basic tenants of NO biology, the association of NO with tumour progression, and the role NO plays in mediating alterations in vascular functions in tumours.

Animals↗

PubMed2006

Overview of anti-VEGF therapy and angiogenesis. Part 1: Angiogenesis inhibition in solid tumor malignancies.

Several new agents that target the vascular endothelial growth factor (VEGF) pathway and inhibit angiogenesis are emerging as promising therapies in multiple cancer types. Bevacizumab, a humanized monoclonal antibody to VEGF-A, is currently approved in combination with intravenous 5-fluorouracil-containing regimens for the first-line treatment of metastatic colorectal cancer and recently demonstrated clinically important results in combination with chemotherapy in patients with non-small cell lung cancer and metastatic breast cancer. Other anti-VEGF agents that have shown benefit in various cancer types will be discussed in this monograph. Despite the often striking results observed with anti-VEGF agents, several unanswered questions remain, such as the optimal duration of therapy and patient selection criteria. These other issues, including the biologic rationale for anti-VEGF therapy, as well as recent clinical trial data with anti-VEGF agents in colorectal, pancreatic, lung, kidney, and brease cancers, are discussed.

Antibodies, Monoclonal↗

PubMed2005

Upregulation of neuropilin-1 by basic fibroblast growth factor enhances vascular smooth muscle cell migration in response to VEGF.

Neuropilin-1 (NRP-1) is a co-receptor for vascular endothelial growth factor (VEGF). During neovascularization, vascular smooth muscle cells (VSMCs) and pericytes modulate the function of endothelial cells. Factors that mediate NRP-1 in human VSMCs (hVSMCs) remain to be elucidated. We studied various angiogenic cytokines to identify factors that increase NRP-1 expression in hVSMCs. Treatment of hVSMCs with basic fibroblast growth factor (b-FGF) induced expressions of NRP-1 mRNA and protein whereas epidermal growth factor, insulin-like growth factor-1, and interleukin-1beta did not. b-FGF induced phosphorylation of Erk-1/2 and JNK. MEK1/2 and nuclear factor kappa B (NF-kappaB) inhibitors (U0126 and TLCK, respectively) blocked the ability of b-FGF to induce NRP-1 mRNA expression, but inhibition of JNK (SP600125) or PI3-kinase activity (wortmannin) did not. Further, the increase in NRP-1 expression by b-FGF enhanced hVSMCs migration in response to VEGF(165). This effect was dependent on the binding of VEGF(165) to VEGFR-2, as blocking antibodies to VEGFR-2, but not VEGFR-1, inhibited VEGF(165)-induced migration. In conclusion, b-FGF increased NRP-1 expression in hVSMCs that in turn enhance the effect of VEGF(165) on cell migration. The enhanced migration of hVSMCs was mediated through binding of VEGF(165) to both NRP-1 and VEGFR-2, as inhibition of VEGFR-2 on these cells blocked the effect of VEGF-mediated cell migration.

Cell Movement↗