Extracellular Engagement of α6 Integrin Inhibited Urokinase-Type Plasminogen Activator–Mediated Cleavage and Delayed Human Prostate Bone Metastasis
Open Access
- 15 June 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (12), 5007-5014
- https://doi.org/10.1158/0008-5472.can-09-0354
Abstract
Expression of α6 integrin, a laminin receptor, on tumor cell surfaces is associated with reduced patient survival and increased metastasis in a variety of tumors. In prostate cancer, tumor extracapsular escape occurs in part via laminin-coated nerves and vascular dissemination, resulting in clinically significant bone metastases. We previously identified a novel form of α6 integrin, called α6p, generated by urokinase-type plasminogen activator-dependent cleavage of the laminin-binding domain from the tumor cell surface. Cleavage increased laminin-dependent migration. Currently, we used the known conformation sensitivity of integrin function to determine if engagement of the extracellular domain inhibited integrin cleavage and the extravasation step of metastasis. We show that α6 integrin was present on prostate carcinoma escaping the gland via nerves. Both endogenous and inducible levels of α6p were inhibited by engaging the extracellular domain of α6 with monoclonal antibody J8H. J8H inhibited tumor cell invasion through Matrigel. A severe combined immunodeficient mouse model of extravasation and bone metastasis produced detectable, progressive osteolytic lesions within 3 weeks of intracardiac injections. Injection of tumor cells, pretreated with J8H, delayed the appearance of metastases. Validation of the α6 cleavage effect on extravasation was confirmed through a genetic approach using tumor cells transfected with uncleavable α6 integrin. Uncleavable α6 integrin significantly delayed the onset and progression of osseous metastases out to six weeks post-injection. The results suggest that α6 integrin cleavage permits extravasation of human prostate cancer cells from circulation to bone and can be manipulated to prevent metastasis. [Cancer Res 2009;69(12):5007–14]This publication has 60 references indexed in Scilit:
- The Role of Alpha 6 Integrin in Prostate Cancer Migration and Bone Pain in a Novel Xenograft ModelPLOS ONE, 2008
- Cancer micrometastasis and tumour dormancyAPMIS, 2008
- Distinct roles of integrins α6 and α4 in homing of fetal liver hematopoietic stem and progenitor cellsBlood, 2007
- β1 integrin activates Rac1 in Schwann cells to generate radial lamellae during axonal sorting and myelinationThe Journal of cell biology, 2007
- Integrin α6 cleavage: A novel modification to modulate cell migrationExperimental Cell Research, 2007
- alpha6 Integrin Cleavage: Sensitizing human prostate cancer to ionizing radiationInternational Journal of Radiation Biology, 2007
- Comparison of reactivity and epitope recognition between sera from American and Italian patients with oral pemphigoidClinical and Experimental Immunology, 2006
- Integrins: Bidirectional, Allosteric Signaling MachinesCell, 2002
- Optical Imaging of Cancer Metastasis to Bone Marrow: A Mouse Model of Minimal Residual DiseaseThe American Journal of Pathology, 2002
- Identification of a Novel Structural Variant of the α6 IntegrinOnline Journal of Public Health Informatics, 2001