Involvement of chemokine receptors in breast cancer metastasis

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.     

The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells

Syk is a protein tyrosine kinase that is widely expressed in haematopoietic cells. It is involved in coupling activated immunoreceptors to downstream signalling events that mediate diverse cellular responses including proliferation, differentiation and phagocytosis. Syk expression has been reported in cell lines of epithelial origin, but its function in these cells remains unknown. Here we show that Syk is commonly expressed in normal human breast tissue, benign breast lesions and low-tumorigenic breast cancer cell lines. Syk messenger RNA and protein, however, are low or undetectable in invasive breast carcinoma tissue and cell lines. Transfection of wild-type Syk into a Syk-negative breast cancer cell line markedly inhibited its tumour growth and metastasis formation in athymic mice. Conversely, overexpression of a kinase-deficient Syk in a Syk-positive breast cancer cell line significantly increased its tumour incidence and growth. Suppression of tumour growth by the reintroduction of Syk appeared to be the result of aberrant mitosis and cytokinesis. We propose that Syk is a potent modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas.     

Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.     

乳腺癌脑转移差异表达基因的生物学功能分析

乳腺癌脑转移(breast cancer brain metastasis,BCBM)的发病机制尚未明确。为了探究BCBM的发病机制,对BCBM差异表达基因的生物学功能进行研究并筛选关键调控基因。从基因表达综合数据库(gene expression omnibus,GEO)下载4个BCBM基因表达谱数据(GSE12237、GSE100534、GSE125989以及GSE43837),采用R语言筛选差异表达基因,采用富集分析包括基因本体分析(gene ontology,GO)和京都基因与基因组百科全书分析(Kyoto encyclopedia of genes and genomes,KEGG)进行生物学功能分析,采用STRING和Cytoscape分析蛋白质相互作用网络,采用Kaplan-Meier进行生存分析。结果表明,同时存在于2个及以上基因表达谱数据中的差异表达基因261个,GO分析主要涉及细胞外基质组织、细胞外结构组织等生物过程,细胞外基质结构组成、胶原结合等分子功能,含有胶原的细胞外基质、胶原蛋白三聚物等细胞组分;KEGG分析主要涉及蛋白质消化和吸收、局部黏附等通路。蛋白质相互作用网络分析得到9个关键调控基因,其中,DCN、COL6A1与BCBM的生存率显著相关,可作为潜在的BCBM关键调控基因,并为BCBM分子机制的研究提供思路。     

LKB1 modulates lung cancer differentiation and metastasis

Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.     

影响胃癌根治术后复发转移的因素

目的探讨影响胃癌根治术后复发转移的因素。方法回顾性分析302例胃癌患者根治术后肿瘤复发转移的情况,并采用Logistlc进行单因素和多因素回归分析。结果本组患者根治术后复发转移率为45．4％,术后2年内复发转移率73．7％,2-5年复发转移率21．％,5年后复发转移率4．4％;单一复发转移占83．2％,多部位复发转移占16．8％。单因素分析显示胃癌根治术后复发转移与肿瘤大小、原发灶部位、癌细胞分化程度、大体分型、癌细胞浸润深度、辅助化疗、术后病理、TNM分期有关,经过多因素回归分析后显示肿瘤大小、辅助化疗、TNN分期为胃癌根治术后复发转移的独立因素。结论胃癌根治术后复发转移大部分在术后2年内,以单一复发转移为主;肿瘤大小、1NM分期及辅助化疗为胃癌根治术后复发转移的独立影响因素。     

影响胃癌根治术后复发转移的因素

目的 探讨影响胃癌根治术后复发转移的因素.方法 回顾性分析302例胃癌患者根治术后肿瘤复发转移的情况,并采用Logistic进行单因素和多因素回归分析.结果 本组患者根治术后复发转移率为45.4%,术后2年内复发转移率73.7%,2～5年复发转移率21.9%,5年后复发转移率4.4%;单一复发转移占83.2%, 多部位复发转移占16.8%.单因素分析显示胃癌根治术后复发转移与肿瘤大小、原发灶部位、癌细胞分化程度、大体分型、癌细胞授润深度、辅助化疗、术后病理、TNN分期有关,经过多因素回归分析后显示肿瘤大小、辅助化疗、TNM分期为胃癌根治术后复发转移的独立因素.结论 胃癌根治术后复发转移大部分在术后2年内,以单一复发转移为主;肿瘤大小、TNM分期及辅助化疗为胃癌根治术后复发转移的独立影响因素.     

Suppression of murine breast cancer metastasis by selective inhibition of CXCR4 by synthetic polypeptide derived from viral macrophage inflammatory protein II

Stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have been implicated in breast cancer metastasis. A significant association between HER2 and CXCR4 expression has been observed in human breast tumor tissues, and overexpression of CXCR4 is essential for HER2-mediated tumor metastasis. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 may limit tumor metastasis. The present study investigated the action of a synthetic antagonist 21-mer peptide derived from viral macrophage inflammatory protein II against CXCR4 (NT21MP) in inhibiting metastasis in vitro and in vivo. The results showed that chemotaxis of SKBR3 cells toward SDF-1α was reduced by NT21MP in a dose-dependent manner (P < 0.05). NT21MP inhibited tumor growth at 500 μg/kg and in combination with Herceptin, the anti-HER2 antibody. The in vivo metastatic assay showed that NT21MP significantly inhibited pulmonary metastasis, and the number of metastatic tumor nodes on the surface of the lung was greatly decreased. Compared with the saline-treated control group, PCNA expression was dose-dependently decreased by NT21MP, the percentage of apoptotic cells was increased, and CXCR4 mRNA and protein expression were downregulated. In conclusion, NT21MP inhibits cellular prolifer-ation, promotes apoptosis by downregulating CXCR4 expression, and suppresses the progression of primary and metastatic tumors. CXCR4 may be a useful therapeutic target for breast cancer, and NT21MP may serve as a potential target drug for the treatment of breast cancer metastasis.     

Regulation of cancer cell migration and bone metastasis by RANKL

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.     

69例肺癌脑转移的治疗及预后分析

目的：探讨肺癌脑转移以放疗为主的综合治疗的疗效及有关因素对预后的影响,方法：对１９８６年６月－１９９６年８月间我院收治收的经头颅ＣＴ和／或ＭＲＩ检查、手术后病理证实的肺癌脑转移６９例进行回顾性分析。结果：手术＋放疗＋化疗、手术＋放疗、放疗＋化疗的中位生存期分别为１１个月、１０．５个月及８．５个月,１年生存率分别为４０．００％,４０．００％及３１．５８５,显著优于单纯手术组、单纯放疗组及单纯化疗组（Ｐ＜０．０５）。原发灶控制、卡氏评份≥６０份、仅有颅内转移病人的１年的生存率分别为２３．６８％、２５．００％及１７．０２％;原发灶未控制、卡氏评分＜６０分、有颅外转移的病人１年生存率分别为２．４４％、０和４．５５％,明显影响预后。结论：肺癌脑转移的治疗中以放疗为主的综合治疗是一种比较合理的治疗方法,可延生长期,提高疗效。