TGF-beta1 secreted by gastric fibroblasts up-regulates CD44H expression and stimulates the peritoneal metastatic ability of scirrhous gastric cancer cells.

Koyama, Tsuyoshi; Yashiro, Masakazu; Inoue, Toru; Nishimura, Shigehiko; Chung, Kyukwang

doi:10.3892/ijo.16.2.355

Cited by 24 publications

(24 citation statements)

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“…5). Stromal fibroblasts up-regulate the CD44 expression of gastric cancer cells via TGFβ signaling, thus resulting in the stimulation of the adhesion ability of scirrhous gastric cancer cells to the mesothelium [39]. The adhesion of cancer cells to the submesothelial components is also an important process in peritoneal dissemination.…”

Section: Adhesion Of Cancer Cells To the Peritoneummentioning

confidence: 99%

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Yashiro

Hirakawa

2010

Cancer Microenvironment

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Fibroblasts play an important role in the progression, growth and spread of gastric cancers. Cancer-stroma interactions have been especially evident in the scirrhous type of gastric carcinoma. Fibroblasts are associated with the cancer progression at the primary and metastatic site. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors produced by organ-specific fibroblasts. Fibroblasts are therefore a key determinant in the malignant progression of gastric cancer and represent an important target for cancer therapies.

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Section: Adhesion Of Cancer Cells To the Peritoneummentioning

confidence: 99%

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Yashiro

Hirakawa

2010

Cancer Microenvironment

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“…[1][2] In the present study, HGF was secreted by NF22 but not by any SGC cells (Table I). Fibroblasts are one of the main components of SGC tissues, and so fibroblasts are important as source of HGF.…”

Section: Figurementioning

confidence: 99%

“…42 Gastric fibroblasts secrete TGF-b1, which up-regulates the expression of an adhesion molecule, CD44H, on SGC cells. 1,20 TGF-b1 also induces morphological changes of the peritoneal mesothelial layer, which enlarges into an extracellular compartment of peritoneal mesothelial cells. 20 This increase exposes collagen and laminin, which are ligands of the integrins under the mesothelial layer, to integrin-rich SGC.…”

Section: Figurementioning

confidence: 99%

“…The interaction of SGC with fibroblasts, i.e., desmoplasia, accelerates tumor progression through the secretion of certain growth factors. [1][2] The combination of NK4 with gefitinib may exert synergistic antitumor effects in the treatment of SGC, because they are essentially different molecular targeting agents. NK4 binds to the c-Met receptor without activation, and competitively antagonizes HGFc-Met-mediated biological activities.…”

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confidence: 99%

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Preclinical study of a “tailor-made” combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa™) for disseminated peritoneal scirrhous gastric cancer

Namiki¹,

Namiki²,

Yoshida³

et al. 2005

Int. J. Cancer

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We evaluated the effect of a ''tailor-made'' chemo-gene therapy in scirrhous gastric cancer (SGC)-bearing nude mice. For this tailormade approach, we first selected gefitinib (epidermal growth factor receptor-tyrosine kinase inhibitor)-sensitive SGC cell lines, and 5/8 cell lines demonstrated various degrees of gefitinib-sensitivity. In the highly gefitinib-sensitive NUGC-4, the biological response to NK4 (HGF antagonist/angiogenesis inhibitor) was examined. Subsequently, the composition of an NK4-expressing ternary complex (cationic lipid/nucleic acid/HMG-1, 2 protein) was optimized for maximum transfection activity in NUGC-4. Finally, mice were peritoneally coinoculated with NUGC-4 and scirrhous-associated gastric fibroblasts, NF22, on day 0. Animal models were orally administrated gefitinib (50 mg/kg/day, on days 7-28), and peritoneally NK4-expressing ternary complex (on days 14, 21 and 28). NK4-expression suppressed the gefitinib-resistance induced by the interaction between fibroblasts and SGC, and eventually, this tailor-made combination synergistically decelerated the disease progression by inhibiting proliferative, angiogenic and antiapoptotic effects in tumor tissues. On day 28, both the hemoglobin concentration (g/dl) (control (n 5 8), 11.9; treated (n 5 8), 17.3; p 5 0.0014) and the numbers of mice in good condition (control, 2; treated, 8; p 5 0.0012) were significantly greater, and the abdominal girth (mm) (control, 81.1; treated, 70.3; p 5 0.0036) was significantly reduced. The median points of bloody ascite-free survival time (days) (control, 22; treated, 44; p < 0.0001) and time to euthanasia (days) (control, 36.5; treated, 56; p < 0.0001) were also significantly prolonged. This combination is a potentially useful approach to the treatment of peritoneal gefitinib-sensitive SGC dissemination. ' 2005 Wiley-Liss, Inc.

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“…These non-fluoropyrimidine nucleosides may potentially help to improve the poor prognosis observed in patients with advanced cancers involving peritoneal dissemination. (Cancer Sci 2007; 98: [11][12][13][14][15][16][17][18] P eritoneal dissemination remains the most difficult type of metastasis to treat, and almost all surgeons believe that an operation is not indicated for such metastasis.…”

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confidence: 99%

Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites

et al. 2006

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Peritoneal dissemination is the most common cause of metastasis from malignancies in the abdominal cavity. There are no standard treatments for peritoneal dissemination and the results are poor. The reasons for this are as follows: (1) no effective chemotherapeutic agents have been identified or developed; (2) surgical cytoreduction has little effect on survival improvement; and (3) the molecular mechanisms of peritoneal dissemination have not been clarified and no therapy against the target molecules has been developed. However, studies on the molecular mechanisms of peritoneal dissemination have elucidated some of the target molecules and the development of new multimodal therapies has also improved survival. Early postoperative intraperitoneal chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and neoadjuvant intraperitoneal-systemic chemotherapy have been newly developed, and a novel surgical therapy named peritonectomy has been proposed to perform complete cytoreduction of peritoneal dissemination. At present, these approaches appear to be effective therapeutic modalities for peritoneal dissemination. However, TS-1 and capecitabine have shown worthwhile results in recent clinical trials for patients with advanced gastric cancer. We recently found that newly developed antitumor cytosine nucleoside analogs show a survival advantage in peritoneal dissemination models using human cancer cells. These non-fluoropyrimidine nucleosides may potentially help to improve the poor prognosis observed in patients with advanced cancers involving peritoneal dissemination. (Cancer Sci 2007; 98: 11-18) P eritoneal dissemination remains the most difficult type of metastasis to treat, and almost all surgeons believe that an operation is not indicated for such metastasis.(1-3) Systemic chemotherapy tends to have little effect on the treatment of peritoneal dissemination, because the peritoneal-blood barrier existing between mesothelial cells and the submesothelial capillary hinders drug distribution throughout the peritoneal cavity. Recent advances in the studies of new drugs and multimodal therapies have proposed the therapeutic potency for advanced cancer with peritoneal dissemination. Neoadjuvant chemotherapy is also known to reduce the tumor burden, thus resulting in a stage reduction. As a result, the incidence of complete cytoreduction may increase after neoadjuvant chemotherapy. A new type of neoadjuvant intraperitoneal-systemic chemotherapy (NIPS) has been developed to increase the rate of complete cytoreduction. The complete removal of peritoneal dissemination is an independent prognostic factor. A peritonectomy is a novel surgical procedure by which complete cytoreduction for peritoneal dissemination is performed.(5-8) These approaches are now being carried out as treatment modalities for peritoneal dissemination from appendiceal, colon and gastric cancer. Furthermore, several recent phase II studies that evaluated the efficacy of new anticancer drugs including taxanes, TS-1 and capecitabine have shown p...

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TGF-beta1 secreted by gastric fibroblasts up-regulates CD44H expression and stimulates the peritoneal metastatic ability of scirrhous gastric cancer cells.

Cited by 24 publications

References 0 publications

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Preclinical study of a “tailor-made” combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa™) for disseminated peritoneal scirrhous gastric cancer

Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites

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