αv‐Integrin isoform expression in primary human tumors and brain metastases

Abstract

To determine whether metastasis to brain is associated with altered expression patterns of integrins, we investigated the expression of avb3, avb5, avb6 and avb8 integrins in primary malignancies and metastases to brain of breast, lung and renal carcinomas and in malignant melanoma. Inhibitors of av integrins are currently in clinical trials for glioblastoma. The role of integrins in the process of brain metastasis from other human tumors is unknown. Immunohistochemistry with novel integrin subtype specific rabbit monoclonal antibodies was performed on tissue microarrays of archival material of surgical biopsies taken from primary tumors and brain metastases. Integrin avb3 expression was increased in brain metastases compared to primary tumors of breast adenocarcinoma, non-small cell lung cancer, renal clear cell cancer and malignant cutaneous melanoma (all p < 0.01). Similarly, integrin avb8 expression was increased in brain metastases compared to primary tumors of breast cancer (p < 0.0001), lung cancer (p < 0.01) and renal cancer (p < 0.0001), with a similar trend in metastatic melanoma. Integrin avb5 was expressed in most primary tumors (98% breast cancer; 67% lung cancer; 90% renal cancer; 89% melanoma) and showed a stronger expression in brain metastases compared to primary tumors from lung cancer and melanoma (p < 0.05). Also integrin avb6 expression was increased in brain metastases compared to primary breast cancer (p < 0.001). Conclusions: The stronger av-integrin expression in brain metastases, especially of avb3 and avb8 integrins, suggests that certain av integrin are involved in the process of brain metastasis. av Integrins may be therapeutic targets for patients with metastatic cancer in brain.Some 45% of cancer patients develop brain metastases during the course of their illness, with 98,000 to 170,000 new cases diagnosed each year in the U.S. alone. 1 There is an increasing prevalence of brain metastases, as primary treatments have become more effective, and people with cancer live longer after initial treatment. Changes in cellular protein levels accompany the metastatic processes, but the molecular details and drivers of the process are unknown for most cancers. These changes allow tumor cells to escape the primary, and to attach and survive at foreign sites, 2,3 which strongly implicates a role for an altered activity of integrins during tumor progression. Integrins are a family of heterodimeric transmembrane glycoproteins that classically bind the extracellular matrix (ECM) to influence cell attachment, motility, cell proliferation, invasion and tumor cell metastasis. 4,5 Several integrin-dependent mechanisms may influence metastasis. Integrins influence tumor cell survival 6 and migration and invasive processes, 7 thereby affecting tumor growth and metastasis. 8 Different integrins in different cellular contexts can either enhance survival or initiate apoptosis. 6,9,10 Although integrins cannot transform cells, several cooperate with oncogenes or receptor tyrosine kinases 6 to influence tum...

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

“…S3). These observations are consistent with those reported in the literature (32,33). The selectivity of the b3 antibody was validated using tumor tissue sections derived from cell lines known to express or lack b3 as determined by flow cytometry.…”

“…In addition, the receptor/ligand pair or the target gene can be substituted when appropriate. The RGD mimetic used in the current study was designed to target integrins overexpressed in some ccRCC patients (32,33). We showed that the efficiency of RGD-DPC delivery to various tumor cells correlated with overall abundance of RGD-binding integrin expression, particularly avb3.…”

“…Our results indicate that RGD-binding integrin expression in tumor cells facilitates efficient delivery of RNAi triggers likely through receptor-mediated internalization. Furthermore, expression of avb3 was reported to correlate with tumor progression and metastasis (32,48), a patient population where alternate treatment over currently available therapies is needed. The RNAi trigger therapeutic payload may be specific to one or more potential target genes.…”

“…The modular nature of DPCs allows for exchange of targeting moiety and RNAi trigger for a specific tissue and therapeutic gene of interest. In this report, we describe an RNAi trigger delivery system that preferentially binds to integrin receptors avb3 and avb5 commonly overexpressed in tumor cells, including ccRCC (31)(32)(33). We demonstrate the targeted delivery of RNAi-mediated HIF2a gene silencing and the resulting proof-of-concept effect on tumor growth inhibition and degeneration in an established orthotopic ccRCC tumor xenograft model.…”

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

“…There is now overwhelming evidence for its role in the clinical progression of multiple human epithelial malignancies (colon, ovary, and brain), both from the in situ to the invasive stage as well as from the invasive stage to regional and distant metastasis 5, 6, 7. The addition of breast cancers to this long list of epithelial cancers where integrin α v β 6 plays a role in clinical progression is more recent.…”