DNA-dependent protein kinase (DNA-PK) plays a major role in the repair of DNA double-strand breaks induced by ionizing radiation (IR). Lack of DNA-PK causes defective DNA double-strand break repair ...and radiosensitization. In general, the cell death induced by IR is considered to be apoptotic. On the other hand, nonapoptotic cell death, autophagy, has recently attracted attention as a novel response of cancer cells to chemotherapy and IR. Autophagy is a protein degradation system characterized by a prominent formation of double-membrane vesicles in the cytoplasm. Little is known, however, regarding the relationship between DNA-PK and IR-induced autophagy. In the present study, we used human malignant glioma M059J and M059K cells to investigate the role of DNA-PK in IR-induced apoptotic and autophagic cell death. Low-dose IR induced massive autophagic cell death in M059J cells that lack the catalytic subunit of DNA-PK (DNA-PKcs). Most M059K cells, the counterpart of M059J cells in which DNA-PKcs are expressed at normal levels, survived, and proliferated although a small portion of the cells underwent apoptosis. Low-dose IR inhibited the phosphorylation of p70(S6K), a molecule downstream of the mammalian target of rapamycin associated with autophagy in M059J cells but not in M059K cells. The treatment of M059K cells with antisense oligonucleotides against DNA-PKcs caused radiation-induced autophagy and radiosensitized the cells. Furthermore, antisense oligonucleotides against DNA-PKcs radiosensitized other malignant glioma cell lines with DNA-PK activity, U373-MG and T98G, by inducing autophagy. The specific inhibition of DNA-PKcs may be promising as a new therapy to radiosensitize malignant glioma cells by inducing autophagy.
The forkhead box M1 (FoxM1) is a key transcription factor regulating multiple aspects of cell biology. Prior studies have shown that FoxM1 is overexpressed in a variety of human tumors, including ...brain tumor, and plays a critical role in cancer development and progression. In this study we found that FoxM1 was up-regulated by heat shock factor 1 (HSF1) under heat shock stress condition in multiple cell lines. Knockdown of HSF1 with HSF1 siRNA or inhibition of HSF1 with a HSF1 inhibitor abrogated heat shock-induced expression of FoxM1. Genetic deletion of HSF1 in mouse embryo fibroblast cells also abolished heat shock stress-induced FoxM1 expression. Moreover, we showed that HSF1 directly bound to FoxM1 promoter and increased FoxM1 promoter activity. Furthermore, we demonstrated that FoxM1 was required for the G2-M phase progression through regulating Cdc2, Cdc20, and Cdc25B under a mild heat shock stress but enhanced cell survival under lethal heat shock stress condition. Finally, in human glioblastoma specimens, FoxM1 overexpression correlated with elevated HSF1 expression. Our results indicate that FoxM1 is regulated by HSF1 and is critical for HSF1-mediated heat shock response. We demonstrated a novel mechanism of stress resistance controlled by HSF1 and a new HSF-FoxM1 connection that mediates cellular thermotolerance.
Background: FoxM1 plays many roles in cancer development, progression, and cancer survival.
Results: FoxM1 is regulated by HSF1 and promotes cell cycle progression and cancer cell survival under heat stress conditions.
Conclusion: FoxM1 is critical for cell survival under heat stress condition.
Significance: HSF1-FoxM1 is a novel connection between heat shock proteins and stress responses and a novel pathway for cell survival under stress condition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose: The signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in most cancers, propagates tumorigenesis,
and is a key regulator of immune suppression in cancer ...patients. We sought to determine the incidence of phosphorylated STAT3
(p-STAT3) expression in malignant gliomas of different pathologic types, whether p-STAT3 expression is a negative prognostic
factor, and whether p-STAT3 expression influences the inflammatory response within gliomas.
Methods: Using immunohistochemical analysis, we measured the incidence of p-STAT3 expression in 129 patients with gliomas of various
pathologic types in a glioma tissue microarray. We categorized our results according to the total number of p-STAT3–expressing
cells within the gliomas and correlated this number with the number of infiltrating T cells and T regulatory cells. We then
evaluated the association between p-STAT3 expression and median survival time using univariate and multivariate analyses.
Results: We did not detect p-STAT3 expression in normal brain tissues or low-grade astrocytomas. We observed significant differences
in the incidence of p-STAT3 expression between the different grades of astrocytomas and different pathologic glioma types.
p-STAT3 expression was associated with the population of tumor-infiltrating immune cells but not with that of T regulatory
cells. On univariate analysis, we found that p-STAT3 expression within anaplastic astrocytomas was a negative prognostic factor.
Conclusions: p-STAT3 expression is common within gliomas of both the astrocytic and oligodendroglial lineages and portends poor survival
in patients with anaplastic astrocytomas. p-STAT3 expression differs significantly between gliomas of different pathologic
types and grades and correlated with the degree of immune infiltration.
The transcription factor Forkhead box M1 (FoxM1) is overexpressed in malignant glioma. However, the functional importance of this factor in human glioma is not known. In the present study, we found ...that FoxM1B was the predominant FoxM1 isoform expressed in human glioma but not in normal brain tissue. The level of FoxM1 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of FoxM1 protein expression in human glioblastoma tissues was inversely correlated with patient survival. Enforced FoxM1B expression caused SW1783 and Hs683 glioma cells, which do not form tumor xenografts, to regain tumorigenicity in nude mouse model systems. Moreover, gliomas that arose from FoxM1B-transfected anaplastic astrocytoma SW1783 cells displayed glioblastoma multiforme phenotypes. Inhibition of FoxM1 expression in glioblastoma U-87MG cells suppressed their anchorage-independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that FoxM1 regulates the expression of Skp2 protein, which is known to promote degradation of the cell cycle regulator p27(Kip1). These results showed that FoxM1 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity. Therefore, FoxM1 might be a new potential target of therapy for human malignant gliomas.
The object of this study was to describe the experience of combining awake craniotomy techniques with high-field (1.5 T) intraoperative MRI (iMRI) for tumors adjacent to eloquent cortex.
From a ...prospective database the authors obtained and evaluated the records of all patients who had undergone awake craniotomy procedures with cortical and subcortical mapping in the iMRI suite. The integration of these two modalities was assessed with respect to safety, operative times, workflow, extent of resection (EOR), and neurological outcome.
Between February 2010 and December 2011, 42 awake craniotomy procedures using iMRI were performed in 41 patients for the removal of intraaxial tumors. There were 31 left-sided and 11 right-sided tumors. In half of the cases (21 50% of 42), the patient was kept awake for both motor and speech mapping. The mean duration of surgery overall was 7.3 hours (range 4.0-13.9 hours). The median EOR overall was 90%, and gross-total resection (EOR ≥ 95%) was achieved in 17 cases (40.5%). After viewing the first MR images after initial resection, further resection was performed in 17 cases (40.5%); the mean EOR in these cases increased from 56% to 67% after further resection. No deficits were observed preoperatively in 33 cases (78.5%), and worsening neurological deficits were noted immediately after surgery in 11 cases (26.2%). At 1 month after surgery, however, worsened neurological function was observed in only 1 case (2.3%).
There was a learning curve with regard to patient positioning and setup times, although it did not adversely affect patient outcomes. Awake craniotomy can be safely performed in a high-field (1.5 T) iMRI suite to maximize tumor resection in eloquent brain areas with an acceptable morbidity profile at 1 month.
Our recent studies have shown that the FoxM1B transcription factor is overexpressed in human glioma tissues and that the level of its expression correlates directly with glioma grade. However, ...whether FoxM1B plays a role in the early development of glioma (i.e., in transformation) is unknown. In this study, we found that the FoxM1B molecule causes cellular transformation and tumor formation in normal human astrocytes (NHA) immortalized by p53 and pRB inhibition. Moreover, brain tumors that arose from intracranial injection of FoxM1B-expressing immortalized NHAs displayed glioblastoma multiforme (GBM) phenotypes, suggesting that FoxM1B overexpression in immortalized NHAs not only transforms the cells but also leads to GBM formation. Mechanistically, our results showed that overexpression of FoxM1B upregulated NEDD4-1, an E3 ligase that mediates the degradation and downregulation of phosphatase and tensin homologue (PTEN) in multiple cell lines. Decreased PTEN in turn resulted in the hyperactivation of Akt, which led to phosphorylation and cytoplasmic retention of FoxO3a. Blocking Akt activation with phosphoinositide 3-kinase/Akt inhibitors inhibited the FoxM1B-induced transformation of immortalized NHAs. Furthermore, overexpression of FoxM1B in immortalized NHAs increased the expression of survivin, cyclin D1, and cyclin E, which are important molecules for tumor growth. Collectively, these results indicate that overexpression of FoxM1B, in cooperation with p53 and pRB inhibition in NHA cells, promotes astrocyte transformation and GBM formation through multiple mechanisms.
A MESSAGE FROM ASCO'S PRESIDENT
As this report demonstrates—and as history shows—investment in clinical cancer research pays off. Since 1990, cancer mortality rates have declined by 15%. Today, two ...thirds of patients survive at least 5 years after diagnosis, compared with just half of patients 40 years ago. Patient quality of life has improved dramatically. In addition, thanks to basic research advances, we are entering an era of personalized cancer medicine, in which treatment is tailored to the unique genetics of the individual. Clinical cancer research is finally receiving an urgently needed boost in investment. For the first time in 5 years, federal funding for research has increased. The economic stimulus package infused billions into short-term biomedical research projects, and President Obama has pledged to invest in “a cure for cancer in our time.” However, despite this progress, cancer remains the number-two killer of Americans. Incidence is projected to nearly double by 2020 as the population grows and ages. Scientifically, cancer is highly complex; it is not one disease, but many, and is increasingly defined by thousands of genetic variations, epigenetic changes, post-transcriptional modifications, and combinations of these mechanisms, rather than by site of origin. Unraveling these complexities begins to explain why some cancers are especially resistant to treatment, a fact we have known for some time. Other cancers are fatal because they are typically diagnosed late in the course of disease, when treatment is less effective. To achieve new breakthroughs, the scale of the national response must match the scale of the problem. Years of flat federal research funding have resulted in abandoned or stalled clinical research projects, a deteriorating research infrastructure, and the loss of talented physicians to other fields. In this report, the American Society of Clinical Oncology (ASCO) commends the recent increases in funding and calls on Congress to make a multiyear commitment to sustained increases in clinical cancer research at the National Institutes of Health and National Cancer Institute. Major advances in cancer treatment cannot be expected to emerge without consistent and predictable investment at the federal level. Although a robust clinical research enterprise is essential to improving patient care, advances mean little if they do not reach people in need. For people with cancer, lack of health insurance can be the difference between life and death. It is estimated that 32% of patients with cancer in the United States are uninsured at some point during their treatment, and more than a quarter opt not to seek treatment as a result. We must end the inequality in health care access. ASCO believes that health care reform must ensure that everyone diagnosed with cancer has the coverage necessary to receive high-quality treatment. To that end, we have made access to cancer care a top priority in our advocacy agenda. I believe the advances described in this report should give all of us cause for hope. Although there is a long road ahead, by investing in a robust national clinical research program and by improving access to high-quality care, we can give every patient the best chance of survival. Douglas Blayney, MD President American Society of Clinical Oncology
Object
Stereotactic radiosurgery (SRS) is commonly used to treat brain metastases. Complications associated with this treatment are underreported. The authors reviewed a large series of patients who ...underwent SRS for brain metastases to identify complications and factors predicting their occurrence.
Methods
Prospectively collected clinical data from 273 patients undergoing SRS for 1 or 2 brain metastases at The University of Texas M. D. Anderson Cancer Center between June 1993 and December 2004 were reviewed. Patients who had received prior treatment for their tumor, including whole-brain radiation, SRS, or surgery, were excluded from the study. Data on adverse neurological and nonneurological outcomes following treatment were collected.
Results
Three hundred sixteen lesions were treated. Complications were associated with 127 (40%) of 316 treated lesions. New neurological complications were associated with 101 (32%) of 316 lesions. The onset of seizure was the most common complication, occurring in 41 (13%) of 316 SRS cases. On multivariate analysis, progressing primary cancer (hazard ratio HR = 2.4, 95% CI 1.6–3.6, p < 0.001), tumor location in eloquent cortex (HR = 2.3, 95% CI 1.6–3.4, p < 0.001), and lower (< 15 Gy) SRS dose (HR = 2.1, 95% CI 1.1–4.2, p = 0.04) were significantly associated with new complications. On multivariate analysis, a tumor location in the eloquent cortex (HR = 2.5, 95% CI 1.6–3.8, p < 0.001) and progressing primary cancer (HR = 1.6, 95% CI 1.1–2.5, p = 0.03) were significantly associated with new neurological complications.
Conclusions
The authors showed that new neurological and nonneurological complications were associated with 40% of SRS treatments for brain metastases. Patients with lesions in functional brain regions have a significantly increased risk of treatment-related complications.
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