Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus.

A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.

[A case of sigmoid colon cancer with a sigmoidovesical fistula treated with preoperative XELOX+bevacizumab therapy and urinary bladder-conserving surgery].

A 64-year-old man presented with abdominal pain, diarrhea, urinary pain, and frequent urination.He was diagnosed with locally advanced sigmoid colon cancer accompanied by a sigmoidovesical fistula, which was determined to require total cystectomy for curative resection.Expecting tumor shrinkage and conservation of the urinary bladder, we performed loop ileostomy followed by preoperative mFOLFOX6+bevacizumab therapy.After 1 course of administration, the implanted port became infected.Therefore, the regimen was changed to 4 courses of XELOX+bevacizumab therapy.After the treatment, there was no longer any evidence of sigmoidovesical fistula.We performed a urinary bladder-conserving sigmoidectomy and finally achieved pathological curative resection.After adjuvant chemotherapy, no findings suggestive of recurrence were noted during 10 postoperative months.Preoperative XELOX+bevacizumab therapy may be worth considering as a therapeutic option for conserving the urinary bladder in cases of locally advanced colon cancer.

His595Tyr polymorphism in the methionine synthase reductase (MTRR) gene is associated with pancreatic cancer risk.

BACKGROUND & AIMS: This study attempts to elucidate a part of the genetic predisposition to the sporadic invasive ductal adenocarcinoma of the pancreas focusing on the genes implicated in the gene-environment interactions in carcinogenesis. METHODS: First, 227 single nucleotide polymorphisms (SNPs) of 46 genes were genotyped on 198 cases and 182 controls. The SNPs, which showed a significant association, were further genotyped on additional samples to perform a joint analysis (total 317 cases vs 1232 controls). The gene selected by joint analysis was resequenced for a high-density SNP typing and a haplotype analysis on 702 cases and 785 controls. Function of the risk and wild-type haplotypes was assessed using cells transfected with complementary DNA (cDNA). RESULTS: The joint analysis with multiple testing adjustment identified 2 SNPs on the methionine synthase reductase (MTRR) gene: rs162049 (intronic SNP), Fisher exact test, P = .0018; OR, 1.33; 95% CI: 1.11-1.60 and rs10380 (His595Tyr), Fisher exact test, P = .0063; OR, 1.45; 95% CI: 1.11-1.88. The SNPs remained significant in the recessive model after the permutation test for multiple testing (rs162049, P = .024; rs10380, P = .023) in the high-density analysis. Stable transfectants of the risk haplotype MTRR cDNA showed significantly elevated homocysteine levels in a culture medium, a lower level of the LINE-1 methylation, and a lower expression of the MTRR protein than did the transfectants with the wild-type haplotype cDNA. CONCLUSIONS: Our study suggested a common missense SNP of the MTRR gene as a novel pancreatic cancer susceptibility factor with a functional significance in folate-related metabolism and the genome-wide methylation status.