Abstract 114: Aberrant integrin alpha v and alpha 5 expression patterns in prostate adenocarcinomas and bone-metastases from prostate cancer are consistent with a bone-colonizing phenotype
Authors: Brendan Connell, Pavel Kopach, Wenying Ren, Raghav Joshi, Steven Naber, Paul Mathew
Journal: Cancer Research (2019)

Abstract Background: Fibronectin-binding αv and α5 integrins mediate homing, adhesive and survival interactions of prostate cancer cells with bone-marrow mesenchymal stromal cells. Monospecific αv integrin antibody therapy slowed progression of bone metastases but failed to impact overall mortality in prostate cancer. Cross-regulation between αv and α5 integrin is a potential source of adaptive resistance to monospecific blockade of either integrin. We assessed the patterns of expression of these partner integrins in bone metastases and the transition from the physiological gland to the malignant phenotype. Methods Formalin-fixed paraffin-embedded (FFPE) radical prostatectomy samples (n=25) from patients with a ≥ Gleason grade 4 component and decalcified FFPE samples of prostate cancer bone metastases (n=10) were obtained from institutional tissue biorepository. Optimized immunohistochemistry methods developed in prostate cancer cell suspensions were applied to assess expression patterns of αv and α5 integrins in benign and malignant glandular elements in primary tumors and bone specimens. Results Integrin αv was universally expressed in the physiological basal layer of benign prostate glands (n=25;100%) but not in the luminal epithelium. With loss of the basal layer in malignant transition, αv expression was recapitulated in 100% of malignant glandular epithelium in distinct patterns including epithelial membranous (24/25;96%), luminal membranous (6/25; 24%), punctate cytoplasmic (14/25;56%), intense foci of membranous staining (single cells or clusters surrounded by αv-negative tumor) (10/25;40%), and rim stromal patterns (14/25;56%). Luminal membranous and rim stromal αv expression patterns were striking in tumors with cribriform morphology. Furthermore, integrin αv was identified in all evaluable bone metastatic samples (7/7:100%). By contrast, integrin α5 was identified infrequently in the physiological basal layer (1/10;10%), was not expressed in malignant glandular epithelium of primary tumors but was paradoxically expressed in malignant epithelium in bone metastases (5/7:71%). Conclusion Integrin αv expression is universally and exclusively found in the physiological basal layer of the normal gland that harbors stem-functions and is recapitulated in high frequency in prostatic adenocarcinomas in diverse patterns suggestive of distinct biological functions that may contribute to disease progression. Co-expression and enrichment of integrins αv and α5 in osseous metastases is supportive of a proposed cooperative role of these fibronectin-binding integrins toward bone colonization. Given the adaptive cross-regulation we have observed with targeting of either integrin, combined αv and α5 integrin targeting in prostate cancer bone metastases may be required for effective therapy. Citation Format: Brendan Connell, Pavel Kopach, Wenying Ren, Raghav Joshi, Steven Naber, Paul Mathew. Aberrant integrin alpha v and alpha 5 expression patterns in prostate adenocarcinomas and bone-metastases from prostate cancer are consistent with a bone-colonizing phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 114.