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ABSTRACT: The aim of this study was to investigate the role of CD24 in the invasiveness of pancreatic ductal adenocarcinoma (PDAC).
We used 2 human PDAC cell lines containing large numbers of CD24-positive (CD24) cells (>65%; AsPC-1 cells) or few CD24 cells (<20%; CFPAC-1 cells). Invasiveness was estimated using the Matrigel invasion assay. The role of CD24 in invasiveness was evaluated using small interference RNA against CD24 mRNA.
The invasive ability of CD24 cells collected by cell sorter was higher than that of CD24-negative (CD24) cells. On the other hand, silencing of CD24 decreased the invasive ability of CD24 cells. Importantly, considerable amount of CD24 cells was converted to CD24 cells within 24 hours under in vitro culture condition. Transforming growth factor β1 significantly inhibited this conversion and consequently maintained the high invasiveness of CD24 cells.
Our data show that CD24 contributes to the invasive ability of PDAC and also suggest that transforming growth factor β1 may contribute to the invasiveness of PDAC by suppressing the conversion from CD24 cells to CD24 cells at the tumor site.
Pancreas 06/2011; 40(7):1034-42. · 2.39 Impact Factor
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Fukuoka igaku zasshi = Hukuoka acta medica 10/2010; 101(10):207-14.
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ABSTRACT: The prognosis of advanced or recurrent colorectal cancer is still poor. Dye-effluxing side population (SP) colon cancer cells are reportedly resistant to chemotherapeutic agents. Most sporadic colorectal cancers involve constitutive activation of the Wnt signaling pathway. In this study, we examined the effect of the Wnt signaling on SP cells and the possibility that inhibition of Wnt signaling may decrease the resistance to chemotherapeutic drugs in the human colon cancer cells.
Drug resistance of SP cells to 5-fluorouracil (5-FU) and irinotecan, decrease of SP cells by the Wnt signaling inhibition and activation of the Wnt signaling of the sorted SP cells were examined using the SW480 colon cancer cell line. mRNA expressions of ATP-binding cassette (ABC) transporters when Wnt signaling was inhibited were evaluated with real-time PCR using colon cancer cell lines (SW480, DLD-1, HCT116, HT29 and LOVO). The sensitivity to irinotecan and paclitaxel when the Wnt signaling was inhibited was investigated using SW480. Inhibition of Wnt signaling was performed by siRNA of beta-catenin.
SP cells showed more resistance to 5-FU and irinotecan, and higher activation of the Wnt signaling pathway, than non-SP cells. Silencing of beta-catenin decreased significantly more SP cells than non-SP cells. Expression of ABC transporter genes, such as ABCB1 and ABCG2, was significantly higher in SP cells than non-SP cells. Silencing of beta-catenin decreased transcription of these ABC transporter genes; beta-catenin-silenced cells became relatively sensitive to paclitaxel and irinotecan.
These results indicate that inhibiting the Wnt signaling pathway may be a fruitful strategy for targeting chemotherapy-resistant colon cancer cells, including SP cells.
Anticancer research 06/2010; 30(6):2041-8. · 1.73 Impact Factor
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Hiroyuki Suzuki, Nobuhito Chikazawa,
Takehiko Tasaka,
Junji Wada,
Akio Yamasaki,
Yoshiki Kitaura,
Masae Sozaki,
Masao Tanaka,
Hideya Onishi,
Takashi Morisaki,
Mitsuo Katano
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ABSTRACT: The human immune system consists of a balance between immune surveillance against non-self antigens and tolerance of self-antigens. CD8(+) T cells and CD4(+) regulatory T cells (Tregs) are the main players for immune surveillance and tolerance, respectively. We examined immunohistochemically the immunological balance at the tumor site using 94 surgically resected colorectal cancer tissues. Forkhead box P3 (FOXP3)(+) cells were considered to be Tregs in the present study. The number of intratumoral FOXP3(+) cells (itFOXP3(+) cells) was positively correlated with lymph node metastases (P = 0.030). itCD8(+) T/itFOXP3(+) cell ratio negatively correlated with pathological stages (P = 0.048). Next, relationship between the number of itCD8(+) T cells or itFOXP3(+) cells and survival prognosis in 94 patients who underwent a curative resection was analyzed. Only itCD8(+) T/itFOXP3(+) cell ratio positively correlated with disease-free survival (0.023) and overall survival (P = 0.010). Multivariate analysis indicated that itCD8(+) T/itFOXP3(+) cell ratio is an independent prognostic factor (P = 0.035) of overall survival. The number of itFOXP3(+) cells positively correlated with transforming growth factor-beta TGF-beta production at the tumor site (P = 0.020). In conclusion, itCD8(+) T/itFOXP3(+) cell ratio is a predictive marker for both disease-free survival time and overall survival time in patients with colorectal cancer. Importantly, itCD8(+) T/itFOXP3(+) cell ratio may be an independent prognostic factor. And, tumor-producing TGF-beta may contribute to the increased number of itFOXP3(+) cells.
Cancer Immunology and Immunotherapy 11/2009; 59(5):653-61. · 3.70 Impact Factor
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Akio Yamasaki,
Chizu Kameda,
Rui Xu,
Haruo Tanaka,
Takehiko Tasaka, Nobuhito Chikazawa,
Hiroyuki Suzuki,
Takashi Morisaki,
Makoto Kubo,
Hideya Onishi,
Masao Tanaka,
Mitsuo Katano
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ABSTRACT: Recently, it was reported that Hh signaling is activated in tumor stromal cells but not in tumor cells themselves and that stromal cells may play a role in the proliferation of cancer cells. This suggests the possibility that stromal cells have an important role in the proliferation of tumor cells that may be mediated through Hh signaling. In this report, we present for the first time that inflammation-stimulated monocytes produce Shh through activation of the NF-kappaB signaling pathway, and that the Shh produced promotes the proliferation of pancreatic cancer cells in a paracrine manner through Hh signaling.
Cancer Immunology and Immunotherapy 10/2009; 59(5):675-86. · 3.70 Impact Factor
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Akio Yamasaki,
Momoko Shoda,
Hiroko Iijima,
Shuntaro Nagai,
Junji Wada,
Hiroyuki Suzuki, Nobuhito Chikazawa,
Takehiko Tasaka,
Chizu Kameda,
Haruo Tanaka,
Mio Ikebe,
Ei Jo,
Norihiro Sato,
Masafumi Nakamura,
Fujio Sekine,
Takashi Morisaki,
Mitsuo Katano
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ABSTRACT: We have reported previously that docetaxel (TXT) induces apoptosis and nuclear factor-kappaB (NF-kappaB) activation, and that blockade of NF-kappaB activation augments TXT-induced apoptosis in human gastric cancer cells. In addition, we have also shown that a protein-bound polysaccharide PSK enhances TXT-induced apoptosis through NF-kappaB inhibition in human pancreatic cancer cells. Based on these observations, in the present study the possibility that PSK could enhance TXT-mediated tumor suppression was examined in vivo and in vitro.
A gastric cancer xenograft model was used to examine the enhanced TXT-mediated tumor suppression by PSK in vivo. The effects of PSK on proliferation and apoptosis induced by TXT in gastric cancer cells were evaluated in vitro using a human gastric cancer cell line, MK-1. The effect of PSK on increased TXT-induced invasion was also measured.
PSK enhanced TXT-mediated tumor suppression in vivo. Immunohistochemical analyses of the tumors revealed that TXT increased NF-kappaB activation in the tumors and this was suppressed by PSK. In the ex vivo experimental system, PSK enhanced the growth inhibition and apoptosis induced by TXT in the MK-1 cells and reduced the increased invasive ability induced by TXT.
PSK enhanced TXT-induced tumor suppression in a gastric cancer xenograft model.
Anticancer research 04/2009; 29(3):843-50. · 1.73 Impact Factor
