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Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases.

Jubb AM, Cesario A, Ferguson M, Congedo MT, Gatter KC, Lococo F, Mulè A, Pezzella F - Br. J. Cancer (2011)

Bottom Line: Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases.However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers.Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Level 4-Academic Block, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK. adrianjubb@gmail.com

ABSTRACT

Background: Anti-angiogenic therapy with bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) predominantly targets immature blood vessels. Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases. However, it is not known whether bevacizumab is effective against brain metastases or whether metastases are representative of their primary in terms of VEGF expression, hypoxia, proliferation and vascular phenotype. The aim of this study was to evaluate these factors in a series of matched primary NSCLCs and brain metastases.

Methods and results: Immunohistochemistry showed strong correlation of carbonic anhydrase 9 expression (a marker of hypoxia) in primary and secondary cancers (P=0.0002). However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers. The mean proportion of mature vessels was 63.2% higher in the brain metastases than the primary tumours (P=0.004). Moreover, the vascular pattern of the primary tumour was not representative of the metastasis.

Conclusions: Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy. These findings may have implications for clinical trials and biomarker studies evaluating anti-angiogenic agents in brain metastases.

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Related in: MedlinePlus

(A) A scatter plot of CD34 Chalkley counts in matched primary (lung) and secondary (brain) cancers. (B) A line plot showing differences in the percentage of blood vessels covered by pericytes in matched primary and secondary cancers. (C) A scatter plot of the percentage of matched primary and secondary cancers positive for carbonic anhydrase 9. (D) A line plot showing differences in the VEGF score in matched primary and secondary cancers. (E, F) Double-labelled immunohistochemistry for CD34 (blue) and smooth muscle actin (brown) in a matched primary (E) and secondary (F) cancer.
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fig1: (A) A scatter plot of CD34 Chalkley counts in matched primary (lung) and secondary (brain) cancers. (B) A line plot showing differences in the percentage of blood vessels covered by pericytes in matched primary and secondary cancers. (C) A scatter plot of the percentage of matched primary and secondary cancers positive for carbonic anhydrase 9. (D) A line plot showing differences in the VEGF score in matched primary and secondary cancers. (E, F) Double-labelled immunohistochemistry for CD34 (blue) and smooth muscle actin (brown) in a matched primary (E) and secondary (F) cancer.

Mentions: Chalkley counts in primary NSCLCs and brain metastases were not significantly correlated (r=0.148, P=0.60) (Table 1; Figure 1). Although, mean Chalkley counts were similar in primary and secondary cancers (42.5 vs 43.5, respectively, P=0.77). The proportion of mature vessels was on average 63.2% greater in brain metastases than their matched primary NSCLCs (mean 25.7% vs 88.9%, respectively, P=0.004) (Table 1; Figure 1). The proportions of mature vessels in primary and secondary cancers were not significantly correlated (r=−0.46, P=0.09). Differences were also observed in vascular patterns, with a predominance of alveolar, basal and diffuse patterns in primary tumours and a predominance of diffuse and papillary patterns in secondary tumours (Table 1).


Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases.

Jubb AM, Cesario A, Ferguson M, Congedo MT, Gatter KC, Lococo F, Mulè A, Pezzella F - Br. J. Cancer (2011)

(A) A scatter plot of CD34 Chalkley counts in matched primary (lung) and secondary (brain) cancers. (B) A line plot showing differences in the percentage of blood vessels covered by pericytes in matched primary and secondary cancers. (C) A scatter plot of the percentage of matched primary and secondary cancers positive for carbonic anhydrase 9. (D) A line plot showing differences in the VEGF score in matched primary and secondary cancers. (E, F) Double-labelled immunohistochemistry for CD34 (blue) and smooth muscle actin (brown) in a matched primary (E) and secondary (F) cancer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111192&req=5

fig1: (A) A scatter plot of CD34 Chalkley counts in matched primary (lung) and secondary (brain) cancers. (B) A line plot showing differences in the percentage of blood vessels covered by pericytes in matched primary and secondary cancers. (C) A scatter plot of the percentage of matched primary and secondary cancers positive for carbonic anhydrase 9. (D) A line plot showing differences in the VEGF score in matched primary and secondary cancers. (E, F) Double-labelled immunohistochemistry for CD34 (blue) and smooth muscle actin (brown) in a matched primary (E) and secondary (F) cancer.
Mentions: Chalkley counts in primary NSCLCs and brain metastases were not significantly correlated (r=0.148, P=0.60) (Table 1; Figure 1). Although, mean Chalkley counts were similar in primary and secondary cancers (42.5 vs 43.5, respectively, P=0.77). The proportion of mature vessels was on average 63.2% greater in brain metastases than their matched primary NSCLCs (mean 25.7% vs 88.9%, respectively, P=0.004) (Table 1; Figure 1). The proportions of mature vessels in primary and secondary cancers were not significantly correlated (r=−0.46, P=0.09). Differences were also observed in vascular patterns, with a predominance of alveolar, basal and diffuse patterns in primary tumours and a predominance of diffuse and papillary patterns in secondary tumours (Table 1).

Bottom Line: Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases.However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers.Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Level 4-Academic Block, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK. adrianjubb@gmail.com

ABSTRACT

Background: Anti-angiogenic therapy with bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) predominantly targets immature blood vessels. Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases. However, it is not known whether bevacizumab is effective against brain metastases or whether metastases are representative of their primary in terms of VEGF expression, hypoxia, proliferation and vascular phenotype. The aim of this study was to evaluate these factors in a series of matched primary NSCLCs and brain metastases.

Methods and results: Immunohistochemistry showed strong correlation of carbonic anhydrase 9 expression (a marker of hypoxia) in primary and secondary cancers (P=0.0002). However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers. The mean proportion of mature vessels was 63.2% higher in the brain metastases than the primary tumours (P=0.004). Moreover, the vascular pattern of the primary tumour was not representative of the metastasis.

Conclusions: Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy. These findings may have implications for clinical trials and biomarker studies evaluating anti-angiogenic agents in brain metastases.

Show MeSH
Related in: MedlinePlus