AIM：To clarify the expression patterns and prognostic implications of the mitotic regulator Polo-like kinase 1 （PLK1） in colon cancer. METHODS： Expression of PLK1 was investigated by immunohistochemistry （158 ca...AIM：To clarify the expression patterns and prognostic implications of the mitotic regulator Polo-like kinase 1 （PLK1） in colon cancer. METHODS： Expression of PLK1 was investigated by immunohistochemistry （158 cases） and immunoblotting in tissue of colon adenomas and adenocarcinomas. PLK1 expression patterns were correlated with clinicopathological parameters and patient prognosis. In addition, expression of PLK1 was evaluated by immunoblot and PCR in colon carcinoma cell lines, and coexpression of PLK1 with the proliferation marker Ki-67 was investigated. RESULTS： Weak PLK1 expression was observed in normal colon mucosa and adenomas. In contrast, 66.7% of carcinomas showed strong expression of PLK1. Overexpression of PLK1 correlated positively with Dukes stage （P〈0.001）, tumor stage （P = 0.001） and nodal status （P〈0.05）. Additionally, PLK1 expression was a prognostic marker in univariate survival analysis （P〈0.01） and had independent prognostic significance （RR = 3.3, P = 0.02） in patients with Iocoregional disease. Expression of PLK1 mRNA and protein was detected in all cell lines investigated. Coexpression of PLK1 and Ki-67 was observed in the majority of colon cancer cells, but a considerable proportion of cells showed PLK1 positivity without Ki-67 expression. CONCLUSION： PLK1 is a new prognostic marker for colon carcinoma patients and may be involved in tumorigenesis and progression of colon cancer. Strategies focusing on PLK1 inhibitionin vivo might therefore represent a promising new therapeutic approach for this tumor entity. 2005 The WIG Press and Elsevier Inc. All rights reserved展开更多
In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute...In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.展开更多
文摘AIM：To clarify the expression patterns and prognostic implications of the mitotic regulator Polo-like kinase 1 （PLK1） in colon cancer. METHODS： Expression of PLK1 was investigated by immunohistochemistry （158 cases） and immunoblotting in tissue of colon adenomas and adenocarcinomas. PLK1 expression patterns were correlated with clinicopathological parameters and patient prognosis. In addition, expression of PLK1 was evaluated by immunoblot and PCR in colon carcinoma cell lines, and coexpression of PLK1 with the proliferation marker Ki-67 was investigated. RESULTS： Weak PLK1 expression was observed in normal colon mucosa and adenomas. In contrast, 66.7% of carcinomas showed strong expression of PLK1. Overexpression of PLK1 correlated positively with Dukes stage （P〈0.001）, tumor stage （P = 0.001） and nodal status （P〈0.05）. Additionally, PLK1 expression was a prognostic marker in univariate survival analysis （P〈0.01） and had independent prognostic significance （RR = 3.3, P = 0.02） in patients with Iocoregional disease. Expression of PLK1 mRNA and protein was detected in all cell lines investigated. Coexpression of PLK1 and Ki-67 was observed in the majority of colon cancer cells, but a considerable proportion of cells showed PLK1 positivity without Ki-67 expression. CONCLUSION： PLK1 is a new prognostic marker for colon carcinoma patients and may be involved in tumorigenesis and progression of colon cancer. Strategies focusing on PLK1 inhibitionin vivo might therefore represent a promising new therapeutic approach for this tumor entity. 2005 The WIG Press and Elsevier Inc. All rights reserved
基金supported by Marga and Walter Boll Stiftung,Deutsche Forschungsgemeinschaft(BR2278/8-1,HU 2795/2-1)TransRegio 332(project A4)Deutsche Krebshilfe and COST Action Mye-Infobank,supported by COST(European Cooperation in Science and Technology).
文摘In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.
