Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment.

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling.

MicroRNA-200c (miR-200c) recently was found to have tumor-suppressive properties by inhibiting the epithelial-mesenchymal transition (EMT) in several cancers. miR-200c also interacts with various cellular signaling molecules and regulates many important signaling pathways. In this study, we investigated the radiosensitizing effect of miR-200c and its mechanism in a panel of human cancer cell lines. Malignant glioma (U251, T98G), breast cancer (MDA-MB-468), and lung carcinoma (A549) cells were transfected with control pre-microRNA, pre-miR-200c, or anti-miR-200c. Then, RT-PCR, clonogenic assays, immunoblotting, and immunocytochemisty were performed. To predict the potential targets of miR-200c, microRNA databases were used for bioinformatics analysis. Ectopic overexpression of miR-200c downregulated p-EGFR and p-AKT and increased the radiosensitivity of U251, T98G, A549, and MDA-MB-468 cells. In contrast, miR-200c inhibition upregulated p-EGFR and p-AKT, and decreased radiation-induced cell killing. miR-200c led to persistent γH2AX focus formation and downregulated pDNA-PKc expression. Autophagy and apoptosis were major modes of cell death. Bioinformatics analysis predicted that miR-200c may be associated with EGFR, AKT2, MAPK1, VEGFA, and HIF1AN. We also confirmed that miR-200c downregulated the expression of VEGF, HIF-1α, and MMP2 in U251 and A549 cells. In these cells, overexpressing miR-200c inhibited invasion, migration, and vascular tube formation. These phenotypic changes were associated with E-cadherin and EphA2 downregulation and N-cadherin upregulation. miR-200c showed no observable cytotoxic effect on normal human fibroblasts and astrocytes. Taken together, our data suggest that miR-200c is an attractive target for improving the efficacy of radiotherapy via a unique modulation of the complex regulatory network controlling cancer pro-survival signaling and EMT.

Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases.

BACKGROUND: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR). METHODS: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined. RESULTS: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition). CONCLUSIONS: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.

Frosted branch angiitis, presumably related to dermatomyositis.

PURPOSE: To report the first case of frosted branch angiitis associated with dermatomyositis in a Korean woman. METHODS: Case report. RESULTS: A 42-year-old woman with history of dermatomyositis presented with unilateral decreased visual acuity. Fundus examination showed findings consistent with frosted branch angiitis. After 1 month of oral prednisolone, the patient made significant visual recovery with near complete resolution of vascular sheathing. CONCLUSIONS: To the best of the authors' knowledge, this is the first case of frosted branch angiitis associated with dermatomyositis. Dermatomyositis should be considered in the differential diagnosis of patients presenting with frosted branch angiitis.

Photodynamic therapy for bilateral subfoveal choroidal neovascularization complicating stargardt macular dystrophy.

PURPOSE: To report the outcome of repeated photodynamic therapy (PDT) for a patient with choroidal neovascularization complicating Stargardt disease. METHODS: Interventional case report. RESULTS: A 41-year-old patient with Stargardt disease developed unilateral choroidal neovascularization treated multiple times with PDT over 2.5 years. At that time, she developed choroidal neovascularization in the fellow eye also treated with PDT. Despite poor interim vision, after >4 years of follow-up, final visual outcome was excellent. CONCLUSION: Our case provides further evidence that repeated PDT may be used for the treatment of choroidal neovascular membrane complicating Stargardt disease without deleterious effects up to 4 years after treatment.

Effects of upper eyelid blepharoplasty on ocular surface sensation and tear production.

BACKGROUND: To evaluate the effect of upper eyelid surgery on ocular surface sensation and tear production. METHODS: Prospective, interventional, consecutive case series. Patients undergoing upper eyelid blepharoplasty or blepharoptosis repair were evaluated with measurements of their corneal sensation and tear production using a Cochet-Bonnet esthesiometer and the Schirmer 1 test without anesthesia, respectively. Measurements were obtained preperatively, and at 1 day and 1 month postoperatively. RESULTS: Eleven patients (21 eyes) were enrolled in the study. There was a significant decrease in corneal sensation between the baseline and postperative day 1 (p < 0.01) and a significant increase between day 1 and month 1 after surgery (p < 0.01). There was no statistically significant difference in corneal sensation between the baseline and postoperative 1 month measurement (p > 0.05). There was no significant difference in tear production between baseline and postoperative day 1 (p > 0.05). There was a statistically significant increase in tear production between baseline and postoperative month 1 (p < 0.05). There was no significant correlation between corneal sensitivity and Schirmer 1 test preoperatively, at postoperative day 1, or at postoperative month 1 after surgery. INTERPRETATION: Upper eyelid surgery results in a temporary decrease in ocular surface sensation that returns to baseline after 1 month. Patients with pre-existing ocular surface dysfunction should consider aggressive treatments with lubricating drops and ointment, punctual occlusion, or anti-inflammatory therapy to accommodate the temporary effects on ocular surface sensation that result from upper eyelid surgery.