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

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; alphav; metastases; prognosis.

Figure 1

Immunohistochemistry of integrin expression (brown color) in primary tumor (first column) and its metastases to the brain (middle column). The third (left) column carries tumor designation and shows a representative HE staining.

Figure 2

Representative Immunohistochemistry of integrin ligands in brain metastases of adenocarcinomas of unknown primary (CUP) showing a strong expression of fibronectin and focal weak expression of Fibrinogen.

Figure 3

Mean immunoreactive scores (IRS) and standard deviation (IRS: 0-12) of αvβ integrin complex expression analyzed in CNS metastases separated for tumor origin.

Figure 4

Mean staining intensity scores (manual, scores 0-2) of αvβ integrin complex and ligand expression in vasculature of (A) carcinoma and (B) melanoma metastases.

Figure 5

Mean staining intensity scores (manual scores 0-2) of αvβ integrin complexes in vasculature of brain carcinoma metastases separated for tumor origin. For combined expression analysis, see Figure 4A.

Figure 6

Scatter plot displaying results of calculated histo-score from automated integrin αvβ analysis separated for tumor origin. N = number of tumors analyzed.