Differential expression of angiopoietin‐2 and vascular endothelial growth factor in androgen‐independent prostate cancer models

Tešan, Tajana; Gustavsson, Heléne; Welén, Karin; Damber, Jan‐Erik

doi:10.1111/j.1464-410x.2008.07768.x

Cited by 15 publications

(14 citation statements)

References 31 publications

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“…This was also confirmed by immunohistochemistry and no significant change in Ang1 protein level was found by either ELISA or IHC (immunohistochemistry; data not shown). Although Ang2 is reported to be mostly secreted by endothelial cells, our data and recent reports from other groups indicate that some tumor cells express high levels of Ang2 protein (22)(23)(24). In addition, we examined CVX-32 dosed intravenously at 15 mg/kg, twice weekly, in staged A549, HT-29, and A431 models that did not express significant amounts of human Ang2 by ELISA or IHC, we observed 17% to 35% TGI (data not shown), suggesting that Ang2 CovX-Bodies could block mouse endothelial derived Ang2 and caused tumor growth inhibition.…”

Section: Ang2 Covx-bodies Reduced the Level Of Ang2 Protein In Tumor contrasting

confidence: 45%

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

132

123

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Purpose: Angiopoietin-1 (Ang1) plays a key role in maintaining stable vasculature, whereas in a tumor Ang2 antagonizes Ang1's function and promotes the initiation of the angiogenic switch. Specifically targeting Ang2 is a promising anticancer strategy. Here we describe the development and characterization of a new class of biotherapeutics referred to as CovX-Bodies, which are created by chemical fusion of a peptide and a carrier antibody scaffold.Experimental Design: Various linker tethering sites on peptides were examined for their effect on CovXBody in vitro potency and pharmacokinetics. Ang2 CovX-Bodies with low nmol/L IC 50 s and significantly improved pharmacokinetics were tested in tumor xenograft studies alone or in combination with standard of care agents. Tumor samples were analyzed for target engagement, via Ang2 protein level, CD31-positive tumor vasculature, and Tie2 expressing monocyte penetration.Results: Bivalent Ang2 CovX-Bodies selectively block the Ang2-Tie2 interaction (IC 50 < 1 nmol/L) with dramatically improved pharmacokinetics (T ½ > 100 hours). Using a staged Colo-205 xenograft model, significant tumor growth inhibition (TGI) was observed (40%-63%, P < 0.01). Ang2 protein levels were reduced by approximately 50% inside tumors (P < 0.01), whereas tumor microvessel density (P < 0.01) and intratumor proangiogenic Tie2 CD11bþ cells (P < 0.05) were significantly reduced. When combined with sunitinib, sorafenib, bevacizumab, irinotecan, or docetaxel, Ang2 CovX-Bodies produced even greater efficacy ($80% TGI, P < 0.01). Conclusion: CovX-Bodies provide an elegant solution to overcome the pharmacokinetic-pharmacodynamic problems of peptides. Long-acting Ang2 specific CovX-Bodies will be useful as single agents and in combination with standard-of-care agents.

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Section: Ang2 Covx-bodies Reduced the Level Of Ang2 Protein In Tumor contrasting

confidence: 45%

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

132

123

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“…13 The stabilization of blood vessels by pericytes also correlates with the difference in vessel morphology, where small thin vessels dominate LNCaP-19 tumours in comparison to LNCaP which more often displays larger vessels with a round shape and a more mature and stabilized appearance. 13,16 The increased MVD of LNCaP-19 has been shown not to depend on an increased expression of VEGF, 13,16 and no increase of any other obvious inducers of endothelial cell proliferation could be identified in an array-based study. 14 Actually, LNCaP-19 induced a lower endothelial proliferation than LNCaP in this study.…”

Section: Discussionmentioning

confidence: 95%

“…14,15 Surprisingly, the expression of one of the major angiogenic growth factors, vascular endothelial growth factor (VEGF), was not increased, which indicates that other mechanisms also might be involved in the regulation of angiogenesis in this subline. 13,16 The present study uses LNCaP and LNCaP-19 to investigate pericyte coverage and its influence on tumour invasion into blood vessels in vivo, as well as tumour cells effects on endothelial cells in vitro, to elucidate the differences between androgendependent and androgen-independent prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Pericyte coverage decreases invasion of tumour cells into blood vessels in prostate cancer xenografts

Welén

Jennbacken

Tešan

et al. 2008

Prostate Cancer Prostatic Dis

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Androgen-independent prostate cancer is an aggressive disease with high angiogenic and metastatic potential. Increased microvessel density and altered invasion properties have previously been described in LNCaP-19, an androgen-independent subline to LNCaP. To characterize the differences in angiogenesis and invasion, the vessels of these tumour xenografts were investigated with immunohistochemistry, and the influence of tumour cells on endothelial cell migration, proliferation and tube formation was studied in vitro. The blood vessels of LNCaP were found to be stabilized by pericytes more frequently than vessels in LNCaP-19. Further, tumour cell invasion was decreased in pericyte-covered blood vessels in both the tumour types. LNCaP-19 displayed an increased potential to induce endothelial cell migration in vitro. In conclusion, pericyte coverage seems to be important for the invasion of tumour cells into blood vessels. Further, LNCaP-19 has lower pericyte coverage and an increased potential to induce endothelial cell migration, which reflects its high microvessel density.

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“…PC-3 cells were obtained from the European Collection of Cell Cultures (ECCC, Wiltshire, UK). Cells were maintained as described previously (Tesan et al 2008).…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

“…RNA quality and concentration were measured using a bioanalyzer (Agilent 2100, Agilent Technologies Inc., Santa Clara, CA, USA) and nanodrop respectively. The RNA was reverse transcribed into cDNA as described previously (Tesan et al 2008).…”

Section: Rna Preparation and Real-time Rt-pcrmentioning

confidence: 99%

N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

Jennbacken¹,

Tešan²,

Wang³

et al. 2010

Endocrine-Related Cancer

Self Cite

116

104

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Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelialmesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.

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Differential expression of angiopoietin‐2 and vascular endothelial growth factor in androgen‐independent prostate cancer models

Cited by 15 publications

References 31 publications

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Pericyte coverage decreases invasion of tumour cells into blood vessels in prostate cancer xenografts

N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

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