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Int J Clin Exp Pathol 2013;6(12):2719-2732

Original Article
Comparing the expression of integrins αvβ3, αvβ5, αvβ6, αvβ8, fibronectin and
fibrinogen in human brain metastases and their corresponding primary tumors

Jens Schittenhelm, Annemarie Klein, Marcos S Tatagiba, Richard Meyermann, Falko Fend, Simon L Goodman, Bence Sipos

Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen 72076, Germany; Department of
Pathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen 72076, Germany; Department of Neurosurgery,
University of Tübingen, Tübingen 72076, Germany; Department of Translational and Biomarkers Research - Oncology, Merck KGaA, 64271
Darmstadt, Germany

Received October 17, 2013; Accepted November 9, 2013; Epub November 15, 2013; Published December 1, 2013

Abstract: Aims: To evaluate the expression of αv-series integrins in brain metastases. Inhibitors targeting these integrins are being tested for
their therapeutic potential. Material and Method: The extracellular regions of the αvβ3, αvβ5, αvβ6, αvβ8, the cytoplasmic domain of β3, the αv-
chain, and the ECM molecules fibronectin and fibrinogen were studied immunohistochemically in a series of 122 carcinoma and 60
melanomas metastatic to the central nervous system. In addition, 38 matched primary and metastatic tumors to the brain were compared
directly. Results: The αv-subunit was generally moderately to highly expressed in most tumors. αvβ3 and cytoplasmic β3 were weakly to
moderately detectable in metastatic renal cell carcinomas and melanomas, αvβ5 was prominently expressed in metastatic renal and colorectal
carcinomas, αvβ6 was most abundantly detectable in metastatic lung adenocarcinomas, but absent in melanomas. The tumor associated
vessels in CNS metastases consistently expressed αvβ3, αvβ5, αv-, fibronectin and fibrinogen, however, mostly at low levels, while αvβ6, αvβ8
were lacking in vasculature. The comparative analysis of 38 matched primary tumors and brain metastases showed comparable levels of
expression only for αvβ3 and αvβ8, while αvβ6 and αvβ5 were higher in primaries. Conclusion: We confirmed that integrin expression exhibits
considerable heterogeneity according to tumor origin. αvβ5 is the most promising target for integrin targeted treatment in brain metastases.

Keywords: Integrins, metastases, prognosis, alphav

Address correspondence to: Dr. Jens Schittenhelm, Department of Neuropathology, Institute of Path-ology and Neuropathology, University
Tuebingen, Calwerstr. 3, D-72076 Tuebingen. Tel: +49-7071-2982283; Fax: +49-7071-294846; E-mail: jens.schittenhelm@med.uni-tuebingen.