Objective:
This update reviews the epidemiology and surgical management, and the controversies of gastric adenocarcinoma. We provide the relevance of outcome data to surgical decision-making and discuss the application of gene-expression analysis to clinical practice.

Gastric adenocarcinoma: review and considerations for future directions.

Cisplatin-based chemotherapy is frequently used to treat advanced gastric cancer (GC). However, the resistance often occurs with the mechanisms being not well understood. Recently, emerging evidence indicates that tumor-associated macrophages (TAMs) play an important role in chemoresistance of cancer. As the important mediators in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins to be involved in tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate cisplatin resistance in gastric cancer. M2 polarized macrophages were obtained from mouse bone marrow or human PBMCs stimulated with IL-4 and IL-13. Exosomes isolated from M2 macrophages culture medium were characterized, and miRNA expression profiles of M2 derived exosomes (M2-exos) were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate M2-exos mediated crosstalk between TAMs and tumor cells. Moreover, the in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. In this study, we showed that M2 polarized macrophages promoted cisplatin (DDP) resistance in gastric cancer cells and exosomes derived from M2 macrophages (M2-exos) are involved in mediating the resistance to DDP. Using miRNA profiles assay, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and cell lysate isolated from M2 polarized macrophage. Functional studies revealed that exosomal miR-21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3K/AKT signaling pathway by down-regulation of PTEN. Our findings suggest that exosomal transfer of tumor-associated macrophages derived miR-21 confer DDP resistance in gastric cancer, and targeting exosome communication may be a promising new therapeutic strategy for gastric cancer patients.

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Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells

Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.

https://www.tandfonline.com/doi/pdf/10.1080/15384101.2015.1005530

Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer

In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies.

PARP inhibitor combination therapy.

Discovery of efficient anti-cancer drug combinations is a major challenge, since experimental testing of all possible combinations is clearly impossible Recent efforts to computationally predict drug combination responses retain this experimental search space, as model definitions typically rely on extensive drug perturbation data We developed a dynamical model representing a cell fate decision network in the AGS gastric cancer cell line, relying on background knowledge extracted from literature and databases We defined a set of logical equations recapitulating AGS data observed in cells in their baseline proliferative state Using the modeling software GINsim, model reduction and simulation compression techniques were applied to cope with the vast state space of large logical models and enable simulations of pairwise applications of specific signaling inhibitory chemical substances Our simulations predicted synergistic growth inhibitory action of five combinations from a total of 21 possible pairs Four of the predicted synergies were confirmed in AGS cell growth real-time assays, including known effects of combined MEK-AKT or MEK-PI3K inhibitions, along with novel synergistic effects of combined TAK1-AKT or TAK1-PI3K inhibitions Our strategy reduces the dependence on a priori drug perturbation experimentation for well-characterized signaling networks, by demonstrating that a model predictive of combinatorial drug effects can be inferred from background knowledge on unperturbed and proliferating cancer cells Our modeling approach can thus contribute to preclinical discovery of efficient anticancer drug combinations, and thereby to development of strategies to tailor treatment to individual cancer patients

/pdf/discovery-of-drug-synergies-in-gastric-cancer-cells-3ax4ssh6w2.pdf

Discovery of Drug Synergies in Gastric Cancer Cells Predicted by Logical Modeling.

Treatment of gastric cancer

The authors study the amount of B cells and serum immunoglobulins in patients with mammary cancer or fibrocystic disease. They indicate that a decreasing in B cells and IgG, and an increasing in IgA are associated with a better prognosis. There is an inverse relation between the level of serum IgG and the blastic transformation of T cells by PHA, what is an indirect measure of the circulating IgG immune complexes. The presence of B cells with IgG in their surfaces makes worse the prognosis.

B cells and serum immunoglobulins in patients with breast pathology

The studies of levels of circulating immunoglobulins in cases of solid neoplasia in man have yielded discordant results, especially in cases of colon and rectal cancer. The possible prognostic value of the quantitation of these parameters has been discussed, and some have even suggested that certain fluctuations in immunoglobulin levels may indicate the development of metastases. We studied the behavior of humoral immunity in 88 patients with gastric adenocarcinoma, 63 patients with cancer of the colon and 60 healthy controls. The cancer patients were grouped according to tumor stage. Serum levels of IgG, IgA and IgM were determined in the preoperative period. The results show a significant decrease in IgG titers in all stages of gastric cancer but more so in the initial stages of development. In the cases of cancer of the colon, the IgG reduction was most evident in the advanced stages of disease. IgA levels were significantly elevated in stage III of gastric cancer and all stages of cancer of the large intestine. IgM levels in gastric cancer behave in a similar manner as IgA, and is elevated in the final stages of cancer of the colon.

Lera Jm

Papers

Treatment of gastric cancer

B cells and serum immunoglobulins in patients with breast pathology

Immunologic study of carcinoma of the digestive tract. Influence of tumor staging. II. Humoral immunity in the preoperative period.