Gastric cancer is the third most lethal cancer worldwide, and evaluation of the genomic status of gastric cancer cells has not translated into effective prognostic or therapeutic strategies.We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), in particular, cancerassociated fibroblasts (CAF). However, very little is known about the role of CAFs in gastric cancer. To address this, we mapped the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from patients with gastric cancer. A stromal gene signature was associated with poor disease outcome, and the transcription factor heat shock factor 1 (HSF1) regulated the signature. HSF1 upregulated inhibin subunit beta A and thrombospondin 2, which were secreted in CAF-derived extracellular vesicles to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment. Significance: This study shows how HSF1 regulates a stromal transcriptional program associated with aggressive gastric cancer and identifies multiple proteins within this program as candidates for therapeutic intervention. better understand the molecular basis of this disease, and to identify 48 biomarkers that may predict outcome and guide therapy.49 Gastric cancer is a heterogeneous disease. Traditionally, anatomical 50 location (true gastric vs. gastro-esophageal) and histologic character-51 istics (diffuse vs. intestinal; tubular vs. papillary) have been used to 52 classify gastric cancer subtypes (2). Recent advances in molecular 53 understanding have enabled classification of gastric cancer into dif-54 ferent subtypes based on chromosomal instability, microsatellite 55 instability, genomic stability, presence of Epstein-Barr virus, and 56 epithelial-mesenchymal transition (EMT), which were associated with 57 different survival outcomes (3-6). Mutations in CDH1 and KRAS, and 58 overexpression of HER2, EGFR, FGFR2, VEGF, were shown to 59 contribute to disease progression and correlate with poor out-60 come (7, 8). Despite serving as valuable guides in deciphering the 61 complexity of gastric cancer, there has been little success in applying 62 these molecular classifiers to treatment stratification and development 63 of targeted therapies (3). Prognosis in the clinic is still mostly evaluated 64 on the basis of TNM staging (tumor size, lymph node involvement, and 65 metastasis), and the standard of care for localized gastric cancer is 66 surgical intervention combined with chemotherapy (7). 67 Increasing evidence over the past decade highlighted the indispens-68 able contribution of the tumor microenvironment (TME) to disease 69 progression and treatment resistance (9). The TME is comprised of 70 various cell types, including endothelial cells, fibroblasts, macro-71 phages, and lymphocytes, as well as extracellular matrix co...
Induction of oral tolerance to colitis-extracted proteins downregulates the anticolon immune response, thereby ameliorating experimental colitis. Suppressor lymphocytes mediate the tolerance by induction of a shift from a proinflammatory to an antiinflammatory immune response.
The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNgamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNgamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance.
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