Brain Tumor Genetic Modification Yields Increased Resistance to Paclitaxel in Physical Confinement.

Loan Bui,Young-Tae Kim,Jamie Wright,Alissa Hendricks,Digant Davé,Cheng-Jen Chuong,Robert Bachoo

doi:10.1038/srep26134

Abstract

Brain tumor cells remain highly resistant to radiation and chemotherapy, particularly malignant and secondary cancers. In this study, we utilized microchannel devices to examine the effect of a confined environment on the viability and drug resistance of the following brain cancer cell lines: primary cancers (glioblastoma multiforme and neuroblastoma), human brain cancer cell lines (D54 and D54-EGFRvIII), and genetically modified mouse astrocytes (wild type, p53−/−, p53−/− PTEN−/−, p53−/− Braf, and p53−/− PTEN−/− Braf). We found that loss of PTEN combined with Braf activation resulted in higher viability in narrow microchannels. In addition, Braf conferred increased resistance to the microtubule-stabilizing drug Taxol in narrow confinement. Similarly, survival of D54-EGFRvIII cells was unaffected following treatment with Taxol, whereas the viability of D54 cells was reduced by 75% under these conditions. Taken together, our data suggests key targets for anticancer drugs based on cellular genotypes and their specific survival phenotypes during confined migration.

Highlights

More than 120 types of primary tumors can occur in the human nervous system, and detrimentally affect the life of many people at all ages[1,2]
For the first part of this study, we evaluated the effects of both physical confinement and Taxol administration on the primary cancers of the nervous system, glioblastoma multiforme (GBM) and neuroblastoma
We found that physical confinement results in a considerable increase in the cell’s resistance to anticancer drug treatment, as revealed in their higher viability when all other factors were kept the same

Summary

Introduction

More than 120 types of primary tumors can occur in the human nervous system, and detrimentally affect the life of many people at all ages[1,2] These effects become more severe in patients with metastatic cancers, which present major challenges in therapeutic treatments. Among all patients suffering from neuroblastomas, more than 50% are diagnosed with metastasis[5] Another example is glioblastoma multiforme (GBM), a grade IV glioma, which has an occurrence of 3.19 per 100,000 people, and represents 16% of all primary brain cancers[6,7]. For the first part of this study, we evaluated the effects of both physical confinement and Taxol administration on the primary cancers of the nervous system, GBM and neuroblastoma. We studied the effects of physical confinement and Taxol administration on mouse astrocytes with different levels of cancerous mutations. We used Doxorubicin (Dox) as the drug model, given that unlike Taxol, which targets microtubule, Dox is toxic mainly for its effects on the DNA of cancer cells[21,22,23,24]

Methods

Results

Discussion

Conclusion