Signalling and functions of angiopoietin-1 in vascular protection

Angiopoietin-1 (Ang1) has powerful vascular protective effects: suppressing plasma leakage, inhibiting vascular inflammation, and preventing endothelial death. Preclinical studies indicate that Ang1 may be therapeutically useful in a number of situations, including treatment of edema, endotoxemia, and transplant arteriosclerosis. However, the ligand has also been implicated in vessel remodeling, induction of angiogenesis and pulmonary hypertension, indicating that strategies to minimize any deleterious effects while optimizing vessel protection are likely to be needed. This review surveys the published data on vascular protective effects of Ang1 and highlights the therapeutic potential of this ligand, as well as possible limitations to its use. We also consider the data on Ang1 receptors and speculate on how to maximize therapeutic benefit by targeting the Tie receptors

Correlation of Ki-67 expression with progression-free and overall survival in mRCC in response to first-line sunitinib.

<p><b>(A)</b> Representative images of tumours with low Ki-67 expression (Ki-67+ nuclei % ≤10%), and high Ki-67 expression (Ki-67+ nuclei % >10%). (<b>B</b>) The distribution of patients according to Ki-67 expression, expressed as the % of Ki-67+nuclei. (<b>C-D</b>) Kaplan-Meier survival curves (Log rank) of progression-free (C) and cancer specific survival (D) in patients with low Ki-67 (blue) and high (green) Ki-67 expression scores. Arrows indicate the magnified areas. Magnifications x200 and x400. Scale bar 40 μm.</p

Association of Ang2 and CD31 expression with sunitinib response in mRCC.

<p>Immunohistochemical staining of mRCC primary tumour tissue using antibodies to Ang2 (<b>A</b>) and CD31 (<b>A, B</b>). (<b>A</b>) Representative images of mRCC tumours with negative (Ang2 = 0), weak (Ang2 = 1), moderate (Ang2 = 2) and high (Ang2 = 3) Ang2 expression scores, and their distribution in the Ang2 low (scores 0 and 1) and Ang2 high categories (scores 2 and 3) (top panel in A). Adjacent sections were stained for CD31 (bottom panel in A, scores not indicated). (<b>B</b>) Representative images of mRCC tumours with negative, weak, moderate (CD31 = 0, CD31 = 1, CD31 = 2) and high (CD31 = 3) CD31 expression scores, and their distribution in the CD31 low (scores 0–2) and CD31 high categories (score 3). (<b>C</b>) The percentage of patients with PR, SD and PD responses according to Ang2 expression scores 0–3, from negative (0) to high (3) expression. (<b>D-E</b>) High Ang2 (D) and high CD31 (E) protein expression in the mRCC tumour vasculature was associated with increased clinical benefit rate (CBR, PR/SD sunitinib responses) using Fisher’s exact test. (<b>F</b>) The percentage of patients with PR, SD and PD responses according to combined Ang2 and CD31 expression. (<b>G</b>) The combination of both high Ang2 and high CD31 protein expression was associated with increased CBR responses using Fisher’s exact test. PR, partial response; SD, stabilized disease; PD, progressive disease. Arrows indicate the magnified areas. Magnifications x100 and x400. Scale bar 80 μm.</p

Patient Characteristics.

<p>Patient Characteristics.</p

Representative immunohistochemical staining of Ang2 in mRCC.

<p><b>(A</b>) immunohistochemical staining of paraffin-embedded mRCC primary tumour tissue using a polyclonal antibody to Ang2. The CD31 expression was scored 3 in the sample. (<b>B</b>) An adjacent section was stained using the polyclonal antibody to Ang2, blocked with a 5-fold molar excess of recombinant human Ang2 (+rhAng2). Arrows indicate the magnified areas. Magnifications x200 and x400. Scale bar 40 μm.</p