CLDN18表达及SNPs在胃癌发生发展中的意义
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摘要
[研究背景]胃癌是世界范围内最常见的恶性肿瘤之一,中国是胃癌高发区域。CLDN18是新近研究发现的与胃癌发生发展可能有关的基因之一,但CLDN18基因在胃癌中的具体表达模式以及与临床病理特征之间的关系尚未阐明。
[目的]探讨CLDN18表达及SNPs与胃癌生物学行为的相关性。
[方法]收集从1991年10月至2007年9月间福建医科大学附属第一医院手术的229例胃癌病例存档蜡块及193例健康体检人群全血样本,采用PCR-LDR方法分析CLDN18基因G15431T和A14158G的基因型以及等位基因频率。收集其中52例于手术切取的新鲜癌组织和癌旁正常组织,采用Real Time PCR方法检测胃癌组织CLDN18基因的mRNA表达水平。收集其中187例存档蜡块,制作组织芯片,应用免疫组织化学方法分析胃癌CLDN18基因蛋白水平的表达。
[结果] 1、胃腺癌组织claudin-18蛋白表达明显低于癌旁正常胃粘膜组织。
2、肠型胃癌claudin-18表达下调率明显高于胃型胃癌和混合型胃癌;浸润至肌层以内的胃癌claudin-18表达下调率明显高于浸润至浆膜及浆膜外组织者。
3、进展期癌侵袭前缘claudin-18表达低于粘膜层癌组织的表达,而淋巴结转移癌高于侵袭前缘的表达。
4、claudin-18表达及表达下调与胃癌患者生存时间之间的关系无显著性意义。
5、52例胃癌CLDN18 mRNA表达水平相对于癌旁正常粘膜组织下调者20例,占38.46%。贲门癌表达量低于非贲门癌;浸润至浆膜层以内的胃癌相对表达量低于浸润至外周组织者;肿瘤直径大于4cm者相对表达量低于小于4cm者。
6、G15431T基因型及等位基因频率在胃癌和正常人群之间有显著性差异,GT+TT基因型人群胃癌患病风险增加1.5267倍。男性人群中CLDN18基因G15431T基因型及等位基因频率在正常对照和胃癌组之间分布具有显著差异性,GT+TT基因型患病风险增加1.6964倍,而女性人群中无明显统计学意义。发现淋巴结转移组、中分化胃癌、肠型胃癌、突破浆膜层胃癌、进展期胃癌以及胃窦部胃癌组的等位基因频率具有显著性差异。
7、男性人群CLDN18基因A14158G基因型及等位基因频率在正常对照和胃癌组之间分布具有显著差异性,AG+GG基因型胃癌患病风险增加2.4982倍。发现贲门组胃癌与正常对照组具有显著性差异。
8、CLDN18基因SNP位点G15431T和A14158G之间无明显的遗传连锁不平衡性。CLDN18基因G15431T和A14158G可能存在基因单体型G-G和T-A分布具有统计学意义。CLDN18基因G15431T和A14158G多态性与胃癌术后生存时间的关系无显著关系。
[结论] 1、Claudin-18表达降低与胃癌的发生有关,肠型胃癌更为显著,提示claudin-18可能参与胃癌型别的维持;
2、进展期胃癌侵袭前缘claudin-18表达具有下调趋势,提示claudin-18表达的丢失是癌细胞侵袭机制之一;
3、淋巴结转移癌中claudin-18表达明显高于侵袭前缘,提示Claudin-18可能参与MET过程。
4、CLDN18基因G15431T多态性与中国男性人群胃癌发病风险有关,并可能影响分化程度、组织分型、临床分期以及发生部位和侵袭转移能力。
5、CLDN18基因A14158G多态性与中国男性人群胃癌发病风险相关,并可能影响发生部位和侵润深度。
6、CLDN18表达及SNPs可能与胃癌预后无关。
[Background] Gastric cancer is one of the most common malignancies worldwide. China is one of the highest incidence regions. CLDN18 gene was identified recently which was related to tumorigenesis and progression of gastric cancer. However, little is known about expression pattern and relationship with clinicopathological features in gastric cancer.
[Objective] To study relationship between expression and SNPs of CLDN18 in gastric carcinoma.
[Methods] A cohort of 229 unrelated gastric cancer cases were accrued from the First Affiliated Hospital of Fujian Medical University from October 1991 to September 2007. 193 healthy controls were recruited from routine check-up people who had no cancer history or family cancer predispositions. PCR-based LDR were used to determine the genotypes of G15431T and A14158G of CLDN18 gene. Of 229 cases, 52 were collected the fresh tumor tissues and the normal tissuses in the distant margin to the tumor at the time of surgery from patients who were undergoing resection of gastric cancers. Real time PCR was conducted to examine the mRNA expression of CLDN18 gene. And 187 archival formalin-fixed paraffin-embedded tissues were collected to make tissue microarray, then immunohistochemistry was performed to detect the expression of claudin-18 protein.
[Results] 1. The expression of claudin-18 was less in gastric carcinoma than in normal tissue.
2. The down-regulation of claudin-18 expression was more in intestinal phenotype GC than in gastric phenotype and mixed phenotype, and that infiltrated into subserous layer than that infiltrated over serous layer.
3. In advanced gastric carcinoma, the expression of claudin-18 in invasive front was less than within mucous layer, and less than in metastatic lymph node.
4. No association was found between expression of claudin-18 and live time of patients.
5. The expression of CLDN18 mRNA was down-regulated in 20 (38.46%) of 52 gastric cancers. A lower expression was found in cancer of gastric cardia compared with non-cardia. The relative expression of CLDN18 mRNA was lower in GC with infiltrion into serous layer and maxial diameter of mass≤4cm than with infiltrion throug whole stomach wall and maxial diameter of mass >4cm.
6. A significant difference that distribution frequency of CLDN18-G15431T genotype and allele frequency was found in the gastric cancer patients and controls. There was a significantly elevated gastric cancer risk (OR, 1.5267) in GT+TT genotype population. Moreover, a elevated risk was observed in men (OR, 1.6964) but in women. Relations between the differences of the genotypes and clinicopathological parameters of gastric cancer patients were found in lymph node metastasis, moderately differentiated, intestinal type, breakthrough the whole stomach wall, advanced cancer and sinus ventriculi group.
7. There was a significant difference of distribution frequency of CLDN18-A14158G genotypes in the gastric cancer male patients from controls. And there was a significantly elevated gastric cancer risk (OR, 2.4982) in AG+GG genotype population. Relations between the differences of the genotypes and clinicopathological parameters of gastric cancer patients were found in cardia cancer group.
8. Linkage equilibrium was observed between G15431T and A14158G. There was a statistic significance in distribution of possible haplotypes G-G and T-A between G15431T and A14158G. No association was found between polymorphisms of G15431T and A14158G and live time of patients.
[Conclusions] 1. Down-regulation of claudin-18 is associated to carcinogenesis of GC,especially intestinal type,which indicated that claudin-18 is involved in maintaining of GC phenotype.
2. A downward trend of claudin-18 expression was presented in invasion front of advanced GC, which indicated that loss of claudin-18 expression may be involved in invasiveness of cancer cells.
3. The expression of claudin-18 in corresponding lymph node metastatic carcinoma was significantly higher than that in invasion front, which suggested that claudin-18 could be involved in MET.
4. CLDN18 G15431T polymorphisms may be associated with the risk of developing gastric cancer in Chinese male population, and influence differentiation, histological typing, location and the invasive and metastatic ability of gastric cancer.
5. CLDN18 A14158G polymorphisms may be associated with the risk of developing gastric cancer in Chinese male population and influence location and infiltrate depth.
6、It should not be deemed that expression and SNPs of claudin-18 affect prognosis of GC
[目的]探讨CLDN18表达及SNPs与胃癌生物学行为的相关性。
[方法]收集从1991年10月至2007年9月间福建医科大学附属第一医院手术的229例胃癌病例存档蜡块及193例健康体检人群全血样本,采用PCR-LDR方法分析CLDN18基因G15431T和A14158G的基因型以及等位基因频率。收集其中52例于手术切取的新鲜癌组织和癌旁正常组织,采用Real Time PCR方法检测胃癌组织CLDN18基因的mRNA表达水平。收集其中187例存档蜡块,制作组织芯片,应用免疫组织化学方法分析胃癌CLDN18基因蛋白水平的表达。
[结果] 1、胃腺癌组织claudin-18蛋白表达明显低于癌旁正常胃粘膜组织。
2、肠型胃癌claudin-18表达下调率明显高于胃型胃癌和混合型胃癌;浸润至肌层以内的胃癌claudin-18表达下调率明显高于浸润至浆膜及浆膜外组织者。
3、进展期癌侵袭前缘claudin-18表达低于粘膜层癌组织的表达,而淋巴结转移癌高于侵袭前缘的表达。
4、claudin-18表达及表达下调与胃癌患者生存时间之间的关系无显著性意义。
5、52例胃癌CLDN18 mRNA表达水平相对于癌旁正常粘膜组织下调者20例,占38.46%。贲门癌表达量低于非贲门癌;浸润至浆膜层以内的胃癌相对表达量低于浸润至外周组织者;肿瘤直径大于4cm者相对表达量低于小于4cm者。
6、G15431T基因型及等位基因频率在胃癌和正常人群之间有显著性差异,GT+TT基因型人群胃癌患病风险增加1.5267倍。男性人群中CLDN18基因G15431T基因型及等位基因频率在正常对照和胃癌组之间分布具有显著差异性,GT+TT基因型患病风险增加1.6964倍,而女性人群中无明显统计学意义。发现淋巴结转移组、中分化胃癌、肠型胃癌、突破浆膜层胃癌、进展期胃癌以及胃窦部胃癌组的等位基因频率具有显著性差异。
7、男性人群CLDN18基因A14158G基因型及等位基因频率在正常对照和胃癌组之间分布具有显著差异性,AG+GG基因型胃癌患病风险增加2.4982倍。发现贲门组胃癌与正常对照组具有显著性差异。
8、CLDN18基因SNP位点G15431T和A14158G之间无明显的遗传连锁不平衡性。CLDN18基因G15431T和A14158G可能存在基因单体型G-G和T-A分布具有统计学意义。CLDN18基因G15431T和A14158G多态性与胃癌术后生存时间的关系无显著关系。
[结论] 1、Claudin-18表达降低与胃癌的发生有关,肠型胃癌更为显著,提示claudin-18可能参与胃癌型别的维持;
2、进展期胃癌侵袭前缘claudin-18表达具有下调趋势,提示claudin-18表达的丢失是癌细胞侵袭机制之一;
3、淋巴结转移癌中claudin-18表达明显高于侵袭前缘,提示Claudin-18可能参与MET过程。
4、CLDN18基因G15431T多态性与中国男性人群胃癌发病风险有关,并可能影响分化程度、组织分型、临床分期以及发生部位和侵袭转移能力。
5、CLDN18基因A14158G多态性与中国男性人群胃癌发病风险相关,并可能影响发生部位和侵润深度。
6、CLDN18表达及SNPs可能与胃癌预后无关。
[Background] Gastric cancer is one of the most common malignancies worldwide. China is one of the highest incidence regions. CLDN18 gene was identified recently which was related to tumorigenesis and progression of gastric cancer. However, little is known about expression pattern and relationship with clinicopathological features in gastric cancer.
[Objective] To study relationship between expression and SNPs of CLDN18 in gastric carcinoma.
[Methods] A cohort of 229 unrelated gastric cancer cases were accrued from the First Affiliated Hospital of Fujian Medical University from October 1991 to September 2007. 193 healthy controls were recruited from routine check-up people who had no cancer history or family cancer predispositions. PCR-based LDR were used to determine the genotypes of G15431T and A14158G of CLDN18 gene. Of 229 cases, 52 were collected the fresh tumor tissues and the normal tissuses in the distant margin to the tumor at the time of surgery from patients who were undergoing resection of gastric cancers. Real time PCR was conducted to examine the mRNA expression of CLDN18 gene. And 187 archival formalin-fixed paraffin-embedded tissues were collected to make tissue microarray, then immunohistochemistry was performed to detect the expression of claudin-18 protein.
[Results] 1. The expression of claudin-18 was less in gastric carcinoma than in normal tissue.
2. The down-regulation of claudin-18 expression was more in intestinal phenotype GC than in gastric phenotype and mixed phenotype, and that infiltrated into subserous layer than that infiltrated over serous layer.
3. In advanced gastric carcinoma, the expression of claudin-18 in invasive front was less than within mucous layer, and less than in metastatic lymph node.
4. No association was found between expression of claudin-18 and live time of patients.
5. The expression of CLDN18 mRNA was down-regulated in 20 (38.46%) of 52 gastric cancers. A lower expression was found in cancer of gastric cardia compared with non-cardia. The relative expression of CLDN18 mRNA was lower in GC with infiltrion into serous layer and maxial diameter of mass≤4cm than with infiltrion throug whole stomach wall and maxial diameter of mass >4cm.
6. A significant difference that distribution frequency of CLDN18-G15431T genotype and allele frequency was found in the gastric cancer patients and controls. There was a significantly elevated gastric cancer risk (OR, 1.5267) in GT+TT genotype population. Moreover, a elevated risk was observed in men (OR, 1.6964) but in women. Relations between the differences of the genotypes and clinicopathological parameters of gastric cancer patients were found in lymph node metastasis, moderately differentiated, intestinal type, breakthrough the whole stomach wall, advanced cancer and sinus ventriculi group.
7. There was a significant difference of distribution frequency of CLDN18-A14158G genotypes in the gastric cancer male patients from controls. And there was a significantly elevated gastric cancer risk (OR, 2.4982) in AG+GG genotype population. Relations between the differences of the genotypes and clinicopathological parameters of gastric cancer patients were found in cardia cancer group.
8. Linkage equilibrium was observed between G15431T and A14158G. There was a statistic significance in distribution of possible haplotypes G-G and T-A between G15431T and A14158G. No association was found between polymorphisms of G15431T and A14158G and live time of patients.
[Conclusions] 1. Down-regulation of claudin-18 is associated to carcinogenesis of GC,especially intestinal type,which indicated that claudin-18 is involved in maintaining of GC phenotype.
2. A downward trend of claudin-18 expression was presented in invasion front of advanced GC, which indicated that loss of claudin-18 expression may be involved in invasiveness of cancer cells.
3. The expression of claudin-18 in corresponding lymph node metastatic carcinoma was significantly higher than that in invasion front, which suggested that claudin-18 could be involved in MET.
4. CLDN18 G15431T polymorphisms may be associated with the risk of developing gastric cancer in Chinese male population, and influence differentiation, histological typing, location and the invasive and metastatic ability of gastric cancer.
5. CLDN18 A14158G polymorphisms may be associated with the risk of developing gastric cancer in Chinese male population and influence location and infiltrate depth.
6、It should not be deemed that expression and SNPs of claudin-18 affect prognosis of GC
引文
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57 D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem, 2005,280(28):26233-40.
58 Roberts-Thomson IC, Butler WJ. Polymorphism and gastric cancer. J Gastroenterol Hepatol, 2005,20(5):793-4.
59 Katoh M. Dysregulation of stem cell signaling network due to germline mutation, SNP, helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol Ther, 2007,6(6):832-9.
60 Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res, 2005,15(2):97-8.
61 Choi YL, Kim J, Kwon MJ, et al. Expression profile of tight junction protein claudin 3 and claudin 4 in ovarian serous adenocarcinoma with prognostic correlation. Histol Histopathol, 2007,22(11):1185-95.
62 Patil N, Berno AJ, Hinds DA, et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science, 2001,294(5547):1719-23.
[1] Costa C, Soares R, Schmitt F. Angiogenesis: Now and then[J]. APMIS, 2004, 112(7-8):402-412.
[2] Tuxhorn J A, McAlhany S J, Dang T D, et al. Stromal cells promote angiogenesis and growth of human prostate tumors in a differential reactive stroma (DRS) xenograft model[J]. Cancer Res, 2002, 62(11): 3298-3307.
[3] Park C C, Bissell M J, Barcellors-Hoff M H. The influence of the microenvironment on the malignant phenotype[J]. Mol Med Today, 2000, 6(8):324-329.
[4] Gabbiani G, Majno G. Dupuytren’s contracture: fibroblast contraction? An ultrastructural study[J]. Am J Pathol, 1972, 66(1):131-146.
[5] Eyden B. The myofibroblast: an assessment of controversial issues and a definition useful in diagnosis and research[J]. Ultrastruct Pathol, 2001, 25(1): 39-50.
[6] Eyden B. Electron microscopy in the study of myofibroblastic lesions[J]. Semin Diagn Pathol, 2003, 20(1): 13-24.
[7] Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation[J]. Exp Cell Res, 1999, 250(2):273-283.
[8] Dugina V, Fontao L, Chaponnier C, et al. Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors[J]. J Cell Sci, 2001, 114(Pt 18),3285-3296.
[9] Lazard D, Sastre X, Frid M G, et al. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue[J].Proc Natl Acad Sci USA, 1993, 90(3): 999–1003.
[10] R?nnov-Jessen L, Villadsen R, Edwards J C, et al. Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts[J]. Am J Pathol, 2002, 161(2):471-480.
[11] Elenbaas B, Weinberg R A. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation[J]. Exp Cell Res, 2001, 264(1):169-184.
[12] Jain M K, Layne M D, Watanabe M, et al. In vitro system for differentiating pluripotent neural crest cells into smooth muscle cells[J]. J Biol Chem, 1998, 273(11):5993-5996.
[13] Lewis M P, Lygoe K A, Nystrom M L, et al. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells[J]. Br J Cancer, 2004, 90(4):822-832.
[14] Tuxhorn J A, Ayala G E, Smith M J, et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling[J]. Clin Cancer Res, 2002, 8(9):2912-2923.
[15] Khouw I M, van Wachem P B, Plantinga J A, et al. TGF-beta and bFGF affect the differentiation of proliferating porcine fibroblasts into myofibroblasts in vitro[J]. Biomaterials, 1999, 20(19):1815-1822.
[16] Direkze N C, Hodivala-Dilke K, Jeffery R, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts[J]. Cancer Res, 2004, 64(23):8492-8495.
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[20] Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J Clin Invest, 2003, 112(12):1776-1784.
[21] Powell D W, Mifflin R C, Valentich J D, et al. Myofibroblasts. I. Paracrine cells important in health and disease[J]. Am J Physiol, 1999, 277(1 Pt 1):C1-9.
[22] Hanamura N, Yoshida T, Matsumoto E, et al. Expression of fibronectin and tenascin-C mRNA by myofibroblasts, vascular cells and epithelial cells in human colon adenomas and carcinomas[J]. Int J Cancer, 1997, 73(1):10-15.
[23] Tuxhorn J A, Ayala G E, Smith M J, et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling[J]. Clin Cancer Res, 2002, 8(9):2912-2923.
[24] Guedj N, Couvelard A, Arcangeli G, et al. Angiogenesis and extracellular matrix remodeling in brochioloalveolar carcinomas: distinctive patterns in mucinous and non-mucinous tumors[J]. Histopathol, 2004, 44(3):251-256.
[25] Walter-Yohrling J, Pratt BM, Ledbetter S, et al. Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model[J]. Cancer Chemother Pharmacol, 2003, 52(4):263-269.
[26] Shao J, Sheng G G, Mifflin R C, et al. Roles of Myofibroblasts in Prostaglandin E2-Stimulated Intestinal Epithelial Proliferation and Angiogenesis[J]. Cancer Res, 2006, 66(2):846-855.
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[28] Tomlinson J, Barsky S H, Nelson S, et al. Different Patterns of Angiogenesis in Sarcomas and Carcinomas[J]. Clin Cancer Res, 1999, 5(11):3516-3522.
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57 D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem, 2005,280(28):26233-40.
58 Roberts-Thomson IC, Butler WJ. Polymorphism and gastric cancer. J Gastroenterol Hepatol, 2005,20(5):793-4.
59 Katoh M. Dysregulation of stem cell signaling network due to germline mutation, SNP, helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol Ther, 2007,6(6):832-9.
60 Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res, 2005,15(2):97-8.
61 Choi YL, Kim J, Kwon MJ, et al. Expression profile of tight junction protein claudin 3 and claudin 4 in ovarian serous adenocarcinoma with prognostic correlation. Histol Histopathol, 2007,22(11):1185-95.
62 Patil N, Berno AJ, Hinds DA, et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science, 2001,294(5547):1719-23.
[1] Costa C, Soares R, Schmitt F. Angiogenesis: Now and then[J]. APMIS, 2004, 112(7-8):402-412.
[2] Tuxhorn J A, McAlhany S J, Dang T D, et al. Stromal cells promote angiogenesis and growth of human prostate tumors in a differential reactive stroma (DRS) xenograft model[J]. Cancer Res, 2002, 62(11): 3298-3307.
[3] Park C C, Bissell M J, Barcellors-Hoff M H. The influence of the microenvironment on the malignant phenotype[J]. Mol Med Today, 2000, 6(8):324-329.
[4] Gabbiani G, Majno G. Dupuytren’s contracture: fibroblast contraction? An ultrastructural study[J]. Am J Pathol, 1972, 66(1):131-146.
[5] Eyden B. The myofibroblast: an assessment of controversial issues and a definition useful in diagnosis and research[J]. Ultrastruct Pathol, 2001, 25(1): 39-50.
[6] Eyden B. Electron microscopy in the study of myofibroblastic lesions[J]. Semin Diagn Pathol, 2003, 20(1): 13-24.
[7] Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation[J]. Exp Cell Res, 1999, 250(2):273-283.
[8] Dugina V, Fontao L, Chaponnier C, et al. Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors[J]. J Cell Sci, 2001, 114(Pt 18),3285-3296.
[9] Lazard D, Sastre X, Frid M G, et al. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue[J].Proc Natl Acad Sci USA, 1993, 90(3): 999–1003.
[10] R?nnov-Jessen L, Villadsen R, Edwards J C, et al. Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts[J]. Am J Pathol, 2002, 161(2):471-480.
[11] Elenbaas B, Weinberg R A. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation[J]. Exp Cell Res, 2001, 264(1):169-184.
[12] Jain M K, Layne M D, Watanabe M, et al. In vitro system for differentiating pluripotent neural crest cells into smooth muscle cells[J]. J Biol Chem, 1998, 273(11):5993-5996.
[13] Lewis M P, Lygoe K A, Nystrom M L, et al. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells[J]. Br J Cancer, 2004, 90(4):822-832.
[14] Tuxhorn J A, Ayala G E, Smith M J, et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling[J]. Clin Cancer Res, 2002, 8(9):2912-2923.
[15] Khouw I M, van Wachem P B, Plantinga J A, et al. TGF-beta and bFGF affect the differentiation of proliferating porcine fibroblasts into myofibroblasts in vitro[J]. Biomaterials, 1999, 20(19):1815-1822.
[16] Direkze N C, Hodivala-Dilke K, Jeffery R, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts[J]. Cancer Res, 2004, 64(23):8492-8495.
[17] Ishii G, Sangai T, Oda T, et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction[J]. Biochem Biophys Res Commun, 2003, 309(1): 232-240.
[18] Friedman S L, Roll F J, Boyles J, et al. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver[J]. Proc Natl Acad Sci U S A, 1985, 82(24):8681-8685.
[19] Johnson S J, Burr A W, Toole K, et al. Macrophage and hepatic stellate cell responses during experimental hepatocarcinogenesis[J]. J Gastroenterol Hepatol, 1998, 13(2):145-151.
[20] Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J Clin Invest, 2003, 112(12):1776-1784.
[21] Powell D W, Mifflin R C, Valentich J D, et al. Myofibroblasts. I. Paracrine cells important in health and disease[J]. Am J Physiol, 1999, 277(1 Pt 1):C1-9.
[22] Hanamura N, Yoshida T, Matsumoto E, et al. Expression of fibronectin and tenascin-C mRNA by myofibroblasts, vascular cells and epithelial cells in human colon adenomas and carcinomas[J]. Int J Cancer, 1997, 73(1):10-15.
[23] Tuxhorn J A, Ayala G E, Smith M J, et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling[J]. Clin Cancer Res, 2002, 8(9):2912-2923.
[24] Guedj N, Couvelard A, Arcangeli G, et al. Angiogenesis and extracellular matrix remodeling in brochioloalveolar carcinomas: distinctive patterns in mucinous and non-mucinous tumors[J]. Histopathol, 2004, 44(3):251-256.
[25] Walter-Yohrling J, Pratt BM, Ledbetter S, et al. Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model[J]. Cancer Chemother Pharmacol, 2003, 52(4):263-269.
[26] Shao J, Sheng G G, Mifflin R C, et al. Roles of Myofibroblasts in Prostaglandin E2-Stimulated Intestinal Epithelial Proliferation and Angiogenesis[J]. Cancer Res, 2006, 66(2):846-855.
[27] Stacker S A, Achen M G, Jussila L, et al. Lymphangiogenesis and cancer metastasis[J]. Nat Rev Cancer, 2002, 2(8):573-583.
[28] Tomlinson J, Barsky S H, Nelson S, et al. Different Patterns of Angiogenesis in Sarcomas and Carcinomas[J]. Clin Cancer Res, 1999, 5(11):3516-3522.
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