Role of Transforming Growth Factor-β1 in Invasion and Metastasis in Gastric Carcinoma

Maehara, Yoshihiko; Kakeji, Yoshihiro; Kabashima, Akira; Emi, Yasunori; Watanabe, Akihiro; Akazawa, Kohei; Baba, Hideo; Kohnoe, Shunji; Sugimachi, Keizō

doi:10.1200/jco.1999.17.2.607

Cited by 153 publications

(110 citation statements)

References 38 publications

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“…It stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor (30). Our result is in accordance with a previous study, reporting an increased TGF-β expression in gastric cancer, which is closely related to invasion and metastasis (31).…”

Section: Discussionsupporting

confidence: 93%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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Abstract. Gastric cancer is one of the most common and lethal malignancies worldwide. Bone metastases in gastric cancer are less common than in other solid tumors, but when they occur the prognosis is generally poor. Increased osteoclastogenesis and osteoclast activity are common features in bone metastases caused by different osteotropic cancer. We investigated osteoclastogenesis and its mechanisms in gastric cancer by enrolling 31 newly diagnosed gastric cancer patients and 45 healthy controls. We studied in vitro osteoclastogenesis in the peripheral blood mononuclear cell cultures of patients and controls, showing spontaneous osteoclastogenesis for half of the patients. This osteoclastogenesis was RANKL-and TNF-α-independent. We analyzed primary tumor and bone metastatic tissues of gastric cancer for the expression of genes involved in osteoclastogenesis. The expression of transforming growth factor-β (TGF-β), osteoprotegerin (OPG), IL-7 and dickkopf-1 (DKK-1) was higher in primary tumors than in bone metastases. RANKL was not detectable in primary tumor or in bone metastatic tissue. The serum RANKL level was significantly higher in healthy controls than in patients, and it was not related to osteoclastogenesis, thereby suggesting that RANKL is not involved in the bone metastatic mechanisms in gastric cancer. We hypothesized a role of RANKL in angiogenesis, thus we compared the serum levels of RANKL to those of VEGF, since VEGF is directly related to angiogenesis. Different from RANKL, the VEGF serum levels were higher in gastric patients than in controls, suggesting a block of the angiogenesis inhibition due to RANKL. RANKL and VEGF serum levels were not predictive of overall survival in our cohort of gastric patients.

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Section: Discussionsupporting

confidence: 93%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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“…Though examples exist in which a cell's proliferative response to TGF-b switches from inhibition to stimulation in parallel with tumor progression (Hsu et al, 1994;Matsuzaki et al, 2000), attenuation of the autocrine loop by decreased expression of the TbRII receptor, leaving intact paracrine signaling to host cells is a frequently-implicated paradigm. Consistent with this formulation of the role of TGF-b in cancer, an association between increased production of TGF-b by tumors and worse clinical outcome has been noted for many epithelial cancers (Gorsch et al, 1992;Takanami et al, 1994;Friedman et al, 1995;Kinugasa et al, 1998;WikstroÈ m et al, 1998;Maehara et al, 1999;Saito et al, 1999). The experiments outlined in this study were designed to contrast in vivo and in vitro consequences of altered tumor cell TGF-b expression and responsiveness, and distinguish between autocrine and paracrine e ects.…”

Section: Discussionmentioning

confidence: 77%

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

et al. 2002

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To characterize the impact of increased production of TGF-b in a xenograft model of human breast cancer, TGF-b-responsive MDA-231 cells were genetically modi®ed by stable transfection so as to increase their production of active TGF-b1. Compared with control cells, cells that produced increased amounts of TGF-b proliferated in vitro more slowly. In vivo, however, tumors derived from these cells exhibited increased proliferation and grew at an accelerated pace. To evaluate the role of autocrine TGF-b signaling, cells were also transfected with a dominant-negative truncated type II TGF-b receptor (TbRII). Disruption of autocrine TGF-b signaling in the TGF-b-overexpressing cells reduced their in vivo growth rate. Co-inoculation of Matrigel with the TGF-b-overexpressing cells expressing the truncated TbRII compensated for their diminished in vivo growth capacity, compared with the TGF-b-overexpressing cells with an intact autocrine loop. Tissue invasion by the tumor was a distinctive feature of the TGF-b-overexpressing cells, whether or not the autocrine loop was intact. Furthermore, tumors derived from TGFb-overexpressing cells, irrespective of the status of the autocrine TGF-b-signaling pathway, had a higher incidence of lung metastasis. Consistent with the suggestion that TGF-b's enhancement of invasion and metastasis is paracrine-based, we observed no signi®cant di erences among the cell clones in an in vitro invasion assay. Thus, in this experimental model system in vitro assays of cell proliferation and invasion do not accurately re¯ect in vivo observations, perhaps due to autocrine and paracrine e ects of TGF-b that in¯uence the important in vivo-based phenomena of tumor growth, invasion, and metastasis.

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“…Several peptide growth factors including epidermal growth factor (EGF) may be involved in its development and/or malignant progression. We reported transforming growth factor b1 (TGFb1) as one of the speci®c molecules secreted from scirrhous gastric carcinoma (Maehara et al, 1999). However, the molecular pathogenesis of this disease has remained to be determined.…”

Section: Introductionmentioning

confidence: 99%