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Gastric Cancer

Gastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer mortality. Depending on tumor characteristics and stage, current treatment modalities include combinations of surgery, chemotherapy, and radiation therapy. However, even with maximal trimodality therapies, prognosis for gastric cancer remains poor, with a 25%-35% 5-year survival rate for loco-regional disease and median survival ranging from 10 to 14 months in advanced disease. Thus, a better understanding of the genetics, biology and molecular mechanisms of gastric cancer would be useful in developing novel targeted approaches for treating this disease.

In gastric cancer, the most commonly recurring genomic aberrations involve PIK3CA, TP53, ErbB2, ErbB3, ARID1A and KRAS. Other less frequent alterations include alterations in FGFR1, MET, MYC and CDH1. Lee et al. sequenced 237 gastric adenocarcinomas (47% diffuse type, 24% EBV positive) uncovering 474 mutations in 41 genes and identifying recurrent somatic mutations in APC, PIK3CA, TP53, STK11, CTNNB1 and CDKN2A, among others. Other groups have similarly reported on recurrent somatic alterations in gastric tumor sets. High-throughput sequencing advances have greatly increased our understanding of the genomic landscape of advanced gastric cancer over the past 3 to 5 years.

Several molecular alterations involving various pathways have been implicated in the development and late-stage progression/metastasis of gastric cancer. For instance, there is emerging evidence that the Wnt signaling pathway may contribute to gastric carcinogenesis through stimulating the migration and invasion of gastric cancer cells. Persons with germ-line mutations in the APC tumor suppressor gene have a 10-fold increased risk of developing gastric cancer when compared with normal persons. β-catenin is frequently mutated in gastric cancer. Activation of the hedgehog pathway is another key mechanism associated with aggressive gastric cancer. The sonic hedgehog (Shh) transcript is restricted to cancer tissue whereas Gli1 and human patched gene 1 (PTCH1) are expressed in cancer cells and the surrounding stroma. The treatment of gastric cancer cells with 3-keto-N-aminoethylaminocaproyldihydrocinnamoyl-cyclopamine, a hedgehog signaling inhibitor, decreases the expression of Gli1 and PTCH1 and leads to cell growth inhibition and apoptosis. The high recombinant Shh-induced migration and invasiveness of gastric cancer cells is mediated by tissue growth factor-beta (TGF-) acting through the ALK5-Smad3 pathway. The expression of lysyl oxidase-like 2 (LOXL2), which can promote tumor cell invasion by the Src kinase/focal adhesion kinase (Src/FAK) pathway, is markedly increased in gastric cancer. The loss of embryonic liver fodrin (ELF) can disrupt TGF-mediated signaling via interfering with the localization of Smad3 and Smad4 and results in the development of gastric cancer.

So far, advances in personalized medicine have improved therapeutic responses in advanced stage ERBB2-positive GC patients treated with trastuzumab. However, this therapy has benefited only ~15% of these patients. New molecules that target the VEGF, PI3K/AKT/mTOR, and MET signaling pathways are also under investigation, and promising results have been obtained. Novel insights regarding signaling pathways that regulate gastric CSCs such as Notch, Hh, and Hippo, and the drugs that block these pathways, also have the potential to improve treatment responses to targeted therapy alone, or in combination with conventional cytotoxic therapy. Creative Biogene, as a leading biotechnology company, is able to offer various gastric cancer pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.

References:

  1. Zhang Z , et al. MicroRNA and signaling pathways in gastric cancer. Cancer Gene Therapy, 2014, 21(8):305-316.
  2. Riquelme I, et al. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget, 2015, 6(28):24750-24779.
  3. Yang W. Targeted therapy for gastric cancer: Molecular pathways and ongoing investigations. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014, 1846(1):232-237.

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