Abstract
New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
Highlights
Glioblastomas (GBMs) belong to the group of high-grade gliomas that are among the most invasive and malignant brain tumors in adults, representing about 15% of all diagnosed brain tumors and affecting three individuals per 100,000 per year [1]
We have reported that integrin α10β1 is present on mesenchymal stem cells (MSCs) and that the expression correlates with the chondrogenic differentiation potential of MSCs [26]
In a xenografted mouse model, we demonstrate that treatment with an antibody–drug conjugate (ADC), composed of the integrin α10 antibody conjugated to the potent cytotoxin saporin [31], anti-α10-SAP, induces cell death of these tumor cells
Summary
Glioblastomas (GBMs) belong to the group of high-grade gliomas that are among the most invasive and malignant brain tumors in adults, representing about 15% of all diagnosed brain tumors and affecting three individuals per 100,000 per year [1]. GBMs have poor prognoses and may be markedly resistant to both radiotherapy and chemotherapy, and no curative treatment is yet available. Standard treatment consists of combinations of maximal neurosurgical resection, reducing tumor burden and pressure on the brain, radiation therapy, and concurrent and continual chemotherapy with temozolomide. The average survival time is just four months from diagnosis. Relapse is anticipated, and with maximal, existing treatment, patient survival is still only about 15 months [3,4,5]
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