![]() 4Department of Urology, UT Southwestern Medical Center, TX, USA. 3Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, TX, USA. 2Advanced Imaging Research Center, UT Southwestern Medical Center, TX, USA. The micro-environment for this study, depicted in Fig. 1, consisted of three different degrees of physical confinement, as follows: narrow confinement (5 by 5 μm in height and width, denoted as 5_5) for observing the cells when they were forced to alter their structure to migrate wide confinement (15 by 15 μm in height and width, denoted as 15_15), where cellsĭepartment of Bioengineering, University of Texas at Arlington, TX, USA. Taxol was chosen as a model anticancer drug due to its known efficacy in the treatment of many cancers, given its effects on microtubule assembly, which results in the apoptosis of tumors16,17. We used engineered Polydimethylsiloxane (PDMS) microfluidic devices to study the effects of Paclitaxel (referred to as Taxol) on primary cancers and genetically modified cell lines in three different physical confinements. Herein, we report the resulting effect of physical confinement on anticancer drug resistance of different cancer cell lines, including those with different stages of carcinogenic mutations. Recent studies of invasive cancers have not only elucidated the mechanisms of cellular adaptation in confinement, such as the change in cell morphology and migration modality10–14 but also emphasized their resistance to many chemotherapeutic drugs15. It is thought that during infiltration through tissues, lymphatic vessels, white matter tracts, etc., cancer cells encounter a specific degree of physical confinement9. In many cases, the tumors become highly malignant and develop secondary cancers8. Despite numerous antitumor drugs, cancer cells remain highly resistant to chemotherapy treatment. Consequently, patients with neuroblastoma or GBM have 5-year survival rates of 59% and 5%, respectively4,7. GBM is the most common type of malignant brain cancer, a finding that is exacerbated by its rapid growth and highly diffuse infiltration6. 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 cancers6,7. Among all patients suffering from neuroblastomas, more than 50% are diagnosed with metastasis5. For instance, neuroblastomas, which are thought to form during the development of the peripheral nervous system3, have been reported to have an occurrence of 10.9 per million children and 52.6 per million infants anually4. These effects become more severe in patients with metastatic cancers, which present major challenges in therapeutic treatments. More than 120 types of primary tumors can occur in the human nervous system, and detrimentally affect the life of many people at all ages1,2. Taken together, our data suggests key targets for anticancer drugs based on cellular genotypes and their specific survival phenotypes during confined migration. 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. In addition, Braf conferred increased resistance to the microtubule-stabilizing drug Taxol in narrow confinement. We found that loss of PTEN combined with Braf activation resulted in higher viability in narrow microchannels. 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). Received: accepted: 27 April 2016 Published: īrain Tumor Genetic Modification Yields Increased Resistance to Paclitaxel in Physical Confinement Loan Bui1, Alissa Hendricks1, Jamie Wright1, Cheng-Jen Chuong1, Digant Davé1,2, Robert Bachoo3 & Young-tae Kim1,4 Brain tumor cells remain highly resistant to radiation and chemotherapy, particularly malignant and secondary cancers.
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