Association of Angiopoietin-2 and Ki-67 Expression with Vascular Density and Sunitinib Response in Metastatic Renal Cell Carcinoma.
The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to anti-angiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.
Comprehensive Cancer Center, Helsinki University Hospital, P.O.B. 180, 00029 HUS, Finland and University of Helsinki, Finland.
Juhana
J
Rautiola
Translational Cancer Biology Program, Research Programs Unit, and Department of Virology, Haartman Institute, Biomedicum Helsinki, Haartmaninkatu 8, P.O.B. 63, FI-00014, University of Helsinki, Finland.
Anita
A
Lampinen
Institute for Molecular Medicine Finland, Haartmaninkatu 8, P.O.B. 63, FI-00014, University of Helsinki, Finland.|Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, P.O.B. 400, FI-00029, HUS, Helsinki, Finland.
Tuomas
T
Mirtti
Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, P.O.B. 400, FI-00029, HUS, Helsinki, Finland.
Ari
A
Ristimäki
Comprehensive Cancer Center, Helsinki University Hospital, P.O.B. 180, 00029 HUS, Finland and University of Helsinki, Finland.
Heikki
H
Joensuu
Comprehensive Cancer Center, Helsinki University Hospital, P.O.B. 180, 00029 HUS, Finland and University of Helsinki, Finland.
Petri
P
Bono
Translational Cancer Biology Program, Research Programs Unit, and Department of Virology, Haartman Institute, Biomedicum Helsinki, Haartmaninkatu 8, P.O.B. 63, FI-00014, University of Helsinki, Finland.|Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290, Helsinki, Finland.
Pipsa
P
Saharinen
D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D015996:Survival Rate; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D019394:Ki-67 Antigen; D011758:Pyrroles; C555023:VPS51 protein, human; D033921:Vesicular Transport Proteins; D000077210:Sunitinib