Immunohistochemical determination of HER-2/neu, c-Kit (CD117), and vascular endothelial growth factor (VEGF) overexpression in malignant melanoma

Potti, Anil; Moazzam, Nauman; Langness, Eric; Sholes, Kaley; Tendulkar, Ketki; Koch, Michaël; Kargas, Steve A.

doi:10.1007/s00432-003-0509-8

Cited by 73 publications

(77 citation statements)

References 28 publications

(35 reference statements)

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“…by guest www.bloodjournal.org From been identified in most primary B-cell lymphoma samples (including marrow samples) and cell lines. 5,6,16 Our data showing that neutralizing this VEGFR-1 pathway reduces the growth of established lymphoma xenografts is also consistent with reports in which the inhibition of VEGFR-1 using genetically modified mice lacking flt-1 kinase domains, 51 exogenous catalytic RNA molecules, 52 or exogenous anti-flt-1 antibody 22 markedly inhibited the growth of breast and epithelial tumors.…”

Section: Discussionsupporting

confidence: 90%

“…3 Previous studies have strongly implicated VEGF and VEGFR in lymphomagenesis. VEGF protein and mRNA have been identified in Hodgkin disease, 4 diffuse large B-cell lymphoma (DLBCL), 5 mantle cell lymphoma, 6 and virus-related lymphomas. 7,8 In indolent lymphoma, increased VEGF expression has been associated with areas of transformation to aggressive DLBCL.…”

Section: Introductionmentioning

confidence: 99%

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Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo

Wang

Teruya‐Feldstein

et al. 2004

Blood

121

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The role of angiogenesis in lymphoproliferative diseases is not well established. We demonstrate here that human lymphoma cells secrete vascular endothelial growth factor (VEGF) and express VEGF receptor 1 (VEGFR-1) and VEGFR-2. Proliferation of non-Hodgkin lymphoma (NHL) cells under serum-free conditions was enhanced by the addition of VEGF and was blocked by VEGFR-1-and VEGFR-2-specific antibodies. To differentiate between VEGF-mediated autocrine and paracrine effects on lymphoma growth, NOD/ SCID mice engrafted with human diffuse large B-cell lymphoma (DLBCL) were treated with species-specific antibodies against human VEGFR-1 (6.12), human VEGFR-2 (IMC-1C11), murine VEGFR-1 (MF-1), or murine VEGFR-2 (DC101). Treatment with 6.12 or DC101 (targeting tumor VEGFR-1 and host VEGFR-2) reduced established DLBCL xenograft growth, whereas treatment with IMC-1C11 or MF-1 (targeting tumor VEGFR-1 and host VEGFR-1) had no effect. Decreased tumor volumes after 6.12 and DC101 treatment correlated with increased tumor apoptosis and reduced vascularization, respectively, supporting the presence of autocrine VEGFR-1-and paracrine VEGFR-2-mediated pathways in lymphomagenesis. Inhibition of paracrine VEGF interactions (DC101) in these models was equivalent to their inhibition with rituximab. Combining DC101 with therapeutic agents (rituximab, 6.12, methotrexate) consistently improved tumor responses over those of single-agent therapy. These data support the further clinical development of VEGFR-targeted approaches for the therapy of aggressive DLBCL. (Blood.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo

Wang

Teruya‐Feldstein

et al. 2004

Blood

121

View full text Add to dashboard Cite

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“…As for soft-tissue sarcomas, higher tumor VEGF expression has been found to be correlated with poor prognosis among several histological types. [28][29][30] In a leiomyosarcoma cell line, critical roles of VEGF in growth and metastasis have been demonstrated. 31 In a large series of soft-tissue sarcomas, Yudoh et al 28 demonstrated that higher VEGF levels in tumor tissue were correlated with higher tumor stage and grade, increased risk of local and distant tumor recurrence, and poor overall survival, whereas Chao et al 32 failed to demonstrate any relationship between VEGF expression and patients' outcome.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

Oda

Tateishi

Matono

et al. 2009

Intl Journal of Cancer

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The expression of chemokine receptor CXCR4 has been associated with poor prognosis and VEGF expression in several kinds of human malignancy. We measured CXCR4 expression levels in soft‐tissue sarcoma and compared them with VEGF expression or microvessel density (MVD). We used real‐time quantitative PCR to examine the CXCR4 and VEGF expression levels in a total 176 tumors, including 24 intermediate tumors, 24 malignant round‐cell tumors (MRCTs) and 128 malignant non‐round‐cell tumors (MNRCTs). We also assessed their immunohistochemical expression of CXCR4 and VEGF, MVD and proliferative activities, as measured by the MIB‐1‐labeling index (LI). Furthermore, we evaluated their significance with respect to patient survival rates in MNRCTs, using the Cox regression model. Within the different types of tumor tissue, the expression levels of CXCR4 (p < 0.0001) and VEGF (p < 0.0001) in MNRCTs were significantly higher than those in intermediate tumors or MRCTs. Immunohistochemical expression levels of CXCR4 and VEGF were significantly correlated with their mRNA expression levels (p < 0.0001). Significant positive correlation was found between CXCR4 and VEGF expression in 112 primary MNRCTs (r = 0.434, p < 0.0001). Moreover, both univariate (p < 0.0001) and Cox multivariate analysis (p = 0.0001) revealed that overexpression of CXCR4 was an independent adverse prognostic factor, in addition to high stage according to the American Joint Committee on Cancer and a high MIB‐1‐LI. Determination of the CXCR4 expression level as a novel marker can provide useful prognostic information for patients and it could be a candidate for molecular targeting therapy in MNRCTs of soft‐tissue sarcomas. © 2008 Wiley‐Liss, Inc.

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“…Sections were dehydrated in graded alcohols (70, 90 and 100% ethanol) before final clearing in xylene and mounting with DPX and glass coverslips. Slides were independently assessed and staining intensity scored (0 to 3 þ ) as has been previously described for VEGF staining in melanoma (Potti et al, 2003(Potti et al, , 2004. Light microscopy examination was performed by three different assessors, blinded to the metastatic outcome of these tumours or identity of the primary antibody.…”

Section: Vegf XXX B Immunohistochemistrymentioning

confidence: 99%

“…A number of studies have attempted to investigate angiogenic growth factors to determine whether they can predict metastasis, but there is poor correlation between the most potent angiogenic factor vascular endothelial growth factor-A (VEGF-A) and metastatic spread (Turley et al, 1998;Straume and Akslen, 2001;Simonetti et al, 2002;Giatromanolaki et al, 2003;Potti et al, 2003Potti et al, , 2004Stefanou et al, 2004;Yang et al, 2004). Expression of VEGF-A is an attractive potential marker of prognosis owing to its consistent upregulation in cancer (Carmeliet, 2000), including melanoma (Bayko et al, 1998;Bayer-Garner et al, 1999), but there are conflicting data surrounding the prognostic implication of any observed upregulation.…”

mentioning

confidence: 99%

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

et al. 2007

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Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis -the growth of new vessels from preexisting vasculature -is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF xxx b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF xxx b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF xxx b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) Po0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGF xxx b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

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Immunohistochemical determination of HER-2/neu, c-Kit (CD117), and vascular endothelial growth factor (VEGF) overexpression in malignant melanoma

Abstract: HER-2/neu has no role in melanogenesis. Both c-Kit (expressed in superficial spreading disease) and VEGF (expressed in amelanotic melanoma) may have significant therapeutic implications as molecular targets, which warrants further investigation.

Cited by 73 publications

References 28 publications

Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo

Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo

Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

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