Molecular biology and immunology of gastric cancer peritoneal metastasis

Yao, Xiaodan; Ajani, Jaffer A.; Song, Shumei

doi:10.21037/tgh.2020.02.08

Cited by 17 publications

(16 citation statements)

References 91 publications

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“…We next implanted control (Vo) and Hpa2 overexpressing MGC-803 cells intra-peritoneal (i.p) and the survival time of the mice was followed. This model is most relevant because peritoneal metastases occur in 55% to 60% of patients with gastric cancer, associating with a low (2%) 5-year overall survival rate [2] . Notably, mice implanted with Hpa2 cells survived significantly longer than mice inoculated with control (Vo) cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Gastric adenocarcinoma is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide; over a million new cases of gastric cancer are diagnosed each year [1] . Despite the use of multiple treatment modalities, including surgery, combined with radiation therapy, chemotherapy, or targeted chemo-immune therapy, the disease often progresses, relapses, or metastasizes and has a 5-year survival rate of less than 35% overall, and only 2% for cases of peritoneal metastases [2] . Thus, better understanding of the disease and the development of new treatment modalities are required to offer patients more effective treatment options.…”

Section: Introductionmentioning

confidence: 99%

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Role of heparanase 2 (Hpa2) in gastric cancer

Liu¹,

Knani²,

Gross-Cohen³

et al. 2021

Neoplasia

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Highlight We report that gastric cancer patients exhibiting high levels of heparanase 2 (Hpa2) survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to overexpress Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. These beneficial effects were found to associate with increased phosphorylation of AMP-activated protein kinase (AMPK) that play an instrumental role in cell metabolism and is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, possibly leading to attenuation of gastric tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu¹,

Knani²,

Gross-Cohen³

et al. 2021

Neoplasia

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“…However, cancer cells either inherently or causatively develop strategies to escape immune surveillance by targeting or hijacking the immune system to assist their abnormal growth by a tumor microenvironment (TME) in which cancer and stromal cells participate. Since immune cells such as macrophages and lymphocytes are present in the greater omentum and lymph nodes, the activation of immune cells would be a promising strategy for treatment of PM [15].…”

Section: Rationalementioning

confidence: 99%

Immunotherapy for Peritoneal Metastases from Gastric Cancer: Rationale, Current Practice and Ongoing Trials

Hispán

Pedregal

Cristóbal

et al. 2021

JCM

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Peritoneal metastases from gastric cancer play a key role in the fatal prognosis of the disease. The lack of efficacy of actual therapeutic approaches together with the outcomes achieved with checkpoint inhibitors in gastric cancer compel us to address the current state-of-the-art immunotherapy treatment of peritoneal dissemination. The immunogenicity of the peritoneum has been described to be particularly active at omentum and peritoneal lymph nodes. Also, both innate and acquired immunity seems to be involved at different molecular levels. Recent works show PDL1 expression being less present at the peritoneal level; however, some clinical trials have begun to yield results. For example, the ATTRACTION-2 trial has demonstrated the activity of Nivolumab in heavily pretreated patients even though peritoneal metastases were diagnosed in a 30% of them. Despite positive results in the metastatic setting, peritoneal responses to systemic checkpoint inhibitors remains unclear, therefore, new strategies for intraperitoneal immunotherapy are being proposed for different ongoing clinical trials.

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“…Treatment options for disseminated gastric cancer may include systemic or hyperthermic intraperitoneal chemotherapy, local radiation, and now more targeted therapies such as immune checkpoint and human epidermal growth factor receptor 2 (HER2) antibodies [2][3][4]. Although patients initially respond to these therapies, the overall longterm outcome remains bleak, with less than 35% overall 5-year survival and only 2% once the disease metastasizes to the peritoneal cavity [5][6][7]. Recently, targeted therapies were approved by the US Food and Drug Administration as a first-line treatment for patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

DUOX2, a New Biomarker for Disseminated Gastric Cancer’s Response to Low Dose Radiation in Mice

Parekh

Solano-González

Martins

et al. 2021

Cancers

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Treatment options are rather limited for gastrointestinal cancer patients whose disease has disseminated into the intra-abdominal cavity. Here, we designed pre-clinical studies to evaluate the potential application of chemopotentiation by Low Dose Fractionated Radiation Therapy (LDFRT) for disseminated gastric cancer and evaluate the role of a likely biomarker, Dual Oxidase 2 (DUOX2). Nude mice were injected orthotopically with human gastric cancer cells expressing endogenous or reduced levels of DUOX2 and randomly assigned to four treatment groups: 1; vehicle alone, 2; modified regimen of docetaxel, cisplatin and 5′-fluorouracil (mDCF) for three consecutive days, 3; Low Dose- Whole Abdomen Radiation Therapy (LD-WART) (5 fractions of 0.15 Gy in three days), 4; mDCF and LD-WART. The combined regimen increased the odds of preventing cancer dissemination (mDCF + LD-WART OR = 4.16; 80% CI = 1.0, 17.29) in the DUOX2 positive tumors, while tumors expressing lower DUOX2 levels were more responsive to mDCF alone with no added benefit from LD-WART. The molecular mechanisms underlying DUOX2 effects in response to the combined regimen include NF-κB upregulation. These data are particularly important since our study indicates that about 33% of human stomach adenocarcinoma do not express DUOX2. DUOX2 thus seems a likely biomarker for potential clinical application of chemopotentiation by LD-WART.

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Molecular biology and immunology of gastric cancer peritoneal metastasis

Cited by 17 publications

References 91 publications

Role of heparanase 2 (Hpa2) in gastric cancer

Role of heparanase 2 (Hpa2) in gastric cancer

Immunotherapy for Peritoneal Metastases from Gastric Cancer: Rationale, Current Practice and Ongoing Trials

DUOX2, a New Biomarker for Disseminated Gastric Cancer’s Response to Low Dose Radiation in Mice

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