Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-KB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo . This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer. (Cancer Res 2006; 66(14): 7176-84)
Transforming growth factor Bs (TGF-B) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-B antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-B antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-B was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-B to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor celltargeted prometastatic activity of TGF-B in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-B antibodies. (Cancer Res 2006; 66(12): 6327-35)
2016): Analysis of light quality and assemblage composition on diatom motility and accumulation rate, Diatom Research,The photosensitive nature of pennate diatom movement has long been observed, with cells being able to change the direction of their movement depending on the light conditions detected at the tips of the cells. However, much of this evidence is based on observations of cells in isolated, single-species culture, thus devoid of any information regarding inter-species interactions that might occur in more complex assemblages. In this study, we tested light-sensitive diatom motility responses (cell accumulation into light spots and high irradiation-induced direction change) in the absence and presence of other species. In the light spot accumulation assay, each species showed characteristic accumulation rates with regard to light irradiance, wavelength, and presence of other species. In mixed-species assemblages, the relative abundance of different species present in the light spot could be directly modified by changes in ambient light conditions. Diatom cells were also irradiated at their leading or trailing ends in the presence or absence of other diatom species to determine the effect of assemblage composition on high irradiance photo-responsiveness. While most multi-species combinations resulted in no significant change in the high irradiance response, Stauroneis phoenicenteron cells showed a significantly slower blue light stimulated direction change response, dependent on relative cell abundance in the presence of Craticula cuspidata. Our experiments thus indicate that the rate of irradiation-stimulated direction change and accumulation ability are not only species-specific and dependent on light wavelength and intensity, but can also be modulated by the presence of other diatom species.
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