Curcumin Changes the Polarity of Tumor-Associated Microglia and Eliminates Glioblastoma

Abstract

Glioblastoma (GBM) is one of the most pernicious forms of cancer and currently chances of survival from this malady are extremely low. We have used the non-invasive strategy of intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of mouse GBM GL261-implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor-associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid-encapsulated formulation of CC, Curcumin Phytosome, into the GL261-implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1^high, iNOS^low M2-type TAM population while inducing the Arginase1^low, iNOS^high M1-type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF-kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state. This article is protected by copyright. All rights reserved.

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Heparan Sulfate Proteoglycans Mediate Renal Carcinoma Metastasis

Abstract

The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow-enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression. This article is protected by copyright. All rights reserved.

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Evaluation the Survival of Patients with Gastric Cancer Treated with Adjuvant or Palliative Chemotherapy

Abstract

Aim

Our aim was to evaluate impact of chemotherapy (5-fluorouracil plus docetaxel and cisplatin) on the survival of gastric cancer cases.

Method

Seventy-nine patients were eligible to take part in this study between November 2006 and April 2013, who received 5-fluorouracil (700 mg/m², 21-h infusion within 5 days), cisplatin (60 mg/m² on day 3), and Docetaxel (60 mg/m² on day 2). Radiotherapy was added to the treatment only in the cases with entire stomach body cancer (positive margin) and with giant ulcer (above 50 mm) in proximal gastric cancer.

Results

Twenty-four patients were female and 55 were male. The median age was 54. In this study, 54 % of the tumors were located in the proximal and 46 % in the distal of stomach. Seventy five percent of patients were at stage I–III (adjuvant chemotherapy), and 25 % at stage IV (palliative chemotherapy). Ninety-one percent of the patients at stages I–II, 68.3 % of the patients at stage III, and one out of 20 patients at stage IV were alive at the end of follow-up. Median disease-free survival for the patients at stages I–III was 63 months, and the overall survival for all patients was 50 months.

Conclusion

The results of our study indicate that the survival of the patients with stomach cancer increases with chemotherapy. Radiotherapy was used for our patients with gastric cancer in specific cases.

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Salivary and serum IL-10, TNF-α, TGF-β, VEGF levels in oropharyngeal squamous cell carcinoma and correlation with HPV and EBV infections

Abstract

Background

Each year approximately 6,000 new cases of head and neck cancer are registered in Poland. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) have been associated with tumour formation. Cytokines have been shown to play an important role both in inflammation and carcinogenesis and they can be detected in saliva and serum with ELISA assays. Salivary biomarkers may be used as markers of early cancer detection.

The aim of this study was the analysis of the serum and salivary levels of IL-10, TNF-α, TGF-β and VEGF in patients with oropharyngeal cancer and in healthy individuals. The level of these biomarkers was also analyzed in HPV- and EBV-related cases.

Methods

The study involved 78 patients with histopathologically confirmed oropharyngeal squamous cell carcinoma and 40 healthy controls. Serum and salivary levels of IL-10, TNF-α, TGF-β and VEGF were analyzed both in patients and in healthy individuals by ELISA method using Diaclone SAS commercially available kits (France). EBV DNA was detected by the nested PCR for amplification of EBNA-2. HPV detection and genotyping was performed using the INNO-LiPA HPV Genotyping Extraassay (Innogenetics N. V, Gent, Belgium). The obtained results were subjected to statistical analysis using Mann–Whitney and Kruskal Wallis tests. Test values of p < 0.05 were considered statistically significant.

Results

The level of tested cytokines was higher in patients than in controls both in serum (IL-10: 2.3 pg/ml vs 1.65 pg/ml, p = 0.0003; TGF-β: 11.3 ng/ml vs 7.8 ng/ml, p = 0.0005; VEGF: 614 pg/ml vs 210 pg/ml, p = 0.0004; TNF-α: 15.0 ng/ml vs 12.90 ng/ml, p = 0.1397) as well as in saliva (IL-10: 5.9 pg/ml vs 2.5 pg/ml, p = 0.00002; TGF-β: 24.1 ng/ml vs 14.8 ng/ml, p = 0.00002; VEGF: 4321 pg/ml vs 280 pg/ml, p = 0.0000; TNF-α: 23.1 ng/ml vs 11.3 ng/ml, p = 0.00002).

EBV DNA was detected in 51.3 % of patients and 20 % of controls, HPV DNA was present in 30.8 % of patients and 2,5 % of controls.

The level of IL-10 was statistically higher in patients infected with EBV, HPV and co-infected with EBV/HPV. The level of TNF-α was significantly higher in patients infected with EBV, while TGF-β in patients with HPV infection and EBV/HPV co-infection.

Conclusion

Detection of salivary cytokines may be very helpful in early diagnosis, treatment and prognosis of OSCC.

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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome

Abstract

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C>T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3933 invasive breast cancer patients, including 101 FANCM c.5101C>T mutation carriers and 3832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1240 breast tumors. The FANCM c.5101C>T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09 – 2.52, P=0.018), with a more pronounced survival effect among familial cases (HR=2.93, 95% CI 1.5 – 5.76, P=1.80x10⁻³). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR=1.8, 95% CI 1.09 – 2.98, P=0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR=3.43, 95% CI 1.6 – 7.34, P=1.50x10⁻³) but not among radiotherapy treated patients (HR=1.35, 95% CI 0.82 – 2.23, P=0.237). Significant interaction was found between the mutation and radiotherapy (P=0.040). Immunohistochemical analyses show that c.5101C>T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C>T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage. This article is protected by copyright. All rights reserved.

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Male pattern baldness and risk of incident skin cancer in a cohort of men

Abstract

We examined the association between male-pattern baldness and risk of incident skin cancer, including invasive melanoma, invasive squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) in a prospective analysis, based on 36,032 participants from the Health Professionals' Follow-up Study. In 1992, participants reported their status of male-pattern baldness at age 45 years by choosing from five crown-view pictograms based on Norwood's classification. Diagnosis of skin cancers was reported biennially and information on melanoma and SCC was pathologically confirmed. We identified 327 melanoma cases, 1324 SCC cases, and 8438 BCC cases during the follow-up. Male-pattern baldness was not significantly associated with risk of incident melanoma, but was significantly associated with increased risk of SCC and BCC. The multivariate-adjusted hazard ratio (HR) (95% confidence interval, CI) for the highest category of baldness (frontal plus severe vertex baldness) was 1.33 (1.06-1.68) for SCC (P_trend=0.001) and 1.23 (1.12-1.35) for BCC(P_trend<0.0001), compared with no baldness. Analyses by body sites found significant associations between frontal plus moderate to severe vertex baldness and risk of melanoma (HR=1.83, 95% CI: 1.01-3.34) and SCC (HR=1.30, 95% CI: 1.02-1.66) at head and neck. The associations were particularly stronger for scalp melanoma (HR=7.15, 95% CI: 1.29-39.42) and scalp SCC (HR=7.09, 95% CI: 3.84-13.08), but not for non-scalp head and neck sites. Information on body sites was not available for BCC. In conclusion, male pattern baldness may be associated with increased risk of skin cancer, but the associations may only exist for those occurring at head and neck, particularly at scalp. This article is protected by copyright. All rights reserved.

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Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma

Abstract

Human renal cancer is extremely resistant to chemotherapy and radiation therapy. This clinical characteristic reduces the efficacy of chemotherapeutic agents in the treatment of recurrence or metastasis following surgical resection. Understanding the mechanism of chemotherapy resistance in renal cell carcinoma remains a significant challenge. In this study, we have shown that varied level of XPF expression was organ-tissue specific by comparing human renal cancer, bladder cancer, testicular cancer and their normal tissue counterparts, respectively. The expression of XPF was significantly higher in renal cancer than in bladder cancer and testicular cancer and correlated with the clinical characteristic of their chemotherapeutics sensitivity. These novel findings proposed that the intrinsic chemoresistance of human renal cell carcinomas might be derived from the high level of XPF expression. In a panel of 5 cancer cell lines, decreasing cisplatin sensitivity correlated with increasing levels of XPF expression. Knockdown of XPF expression not only increased sensitivity of renal carcinoma cells to cisplatin treatment by affecting the DNA damage response, including DNA repair, cell cycle regulation and apoptosis, but also increased senescence of renal cancer cell. Furthermore, experiment in vivo confirmed that silenced XPF significantly increased the sensitivity and survival following treatment with cisplatin in xenograft mice bearing renal cell tumor. These findings firstly uncover a partial mechanism of intrinsic chemoresistance in renal cancer and may provide a new approach to break through the obstacle of intrinsic chemoresistance by targeting the XPF protein with a potential new inhibitor. This article is protected by copyright. All rights reserved.

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