细胞粘附分子的表达与结直肠癌转移、预后的关系

细胞粘附分子是参与细胞－细胞以及细胞－基质之间作用的一类粘附物质的总称,包括钙粘附素族,整合素族,免疫球蛋白超家族,选择素族,透明质酸受体类及其它。近年来细胞粘附分子在肿瘤转移中的作用日益引起人们的重视。本文就主要几种粘附分子的表达与结直肠癌转移,预后的关系的研究进展作一综述。     

与结肠癌转移倾向相关的细胞粘附基因的筛查

目的： 利用cDNA基因芯片研究已发生转移与未发生转移的原发性结肠癌基因表达谱的差异,筛选与结肠癌转移相关的细胞粘附基因。方法：分别提取未发生转移及已发生转移的原发性结肠癌组织mRNA,逆转录成cDNA探针,经Cy3和Cy5标记后与含1.6万余点的cDNA基因芯片杂交,用专用软件分析杂交信号强度,找出与细胞粘附相关的差异基因,并进行功能分析。结果：已发生转移与未发生转移的原发性结肠癌基因表达谱有显著差异,与细胞粘附相关的基因中,荧光强度比值小于0.2或大于5.0的差异基因共26个。上调基因15个,包括CD44、ICAM1、NCAM、HMGB1、SELL、CHRNA5、CEACAM6、VCAM1、HMGA2、PECAM1、CEACAM1、CD18、ITGAL、TGFB1、ICAM-3。下调基因11个,包括CD99、CADM1、CD82、F11R、SELE、CD226、TSLC1、PTB、CAR、JAM-2、PTEN。结论：结肠癌转移是由多个基因参与的复杂过程,细胞粘附基因在转移过程中起着非常重要的作用。     

On the role of cell surface carbohydrates and their binding proteins (lectins) in tumor metastasis

This review focuses on the recent advances in investigations of the role of cell surface carbohydrates in tumor metastasis. It also summarizes the results of extensive studies of endogenous lectins, their structure, carbohydrate specificity and biological functions with the major emphasis on the significance of lectin–cell surface carbohydrate interactions in a metastatic process. Numerous data demonstrate that malignant transformation is associated with various and complex alterations in the glycosylation process. Some of these changes might provide a selective advantage for tumor cells during their progression to more invasive and metastatic phenotype. Cell glycosylation depends on the expression and function of various glycosyltransferases and glycosidases. Recently, transfection of genes encoding various glysosyltransferases gene in sense and antisense orientation helped to bring direct evidence that changes in cell surface carbohydrates are important for the metastatic behavior of tumor cells. Cell surface carbohydrates affect tumor cell interactions with normal cells or with the extracellular matrix during metastatic spread and growth. These interactions can be mediated via tumor cell carbohydrates and their binding proteins known as endogenous lectins. The family of the discovered endogenous lectins is rapidly expanding. The number of C-type lectins has reached 50 and at least 10 galectins have been identified. The biological significance of the endogenous lectins and their possible role in tumor growth and metastasis formation has started to unravel. Some lectins recognize the 'foreign' patterns of cell surface carbohydrates expressed by microorganisms and tumor cells, and play a role in innate and adaptive immunity. It was shown that lectins affect tumor cell survival, adhesion to the endothelium or extracellular matrix, as well as tumor vascularization and other processes that are crucial for metastatic spread and growth.     

细胞黏附分子在肝癌复发转移中的作用研究进展

细胞黏附分子（CAMs）是位于细胞表面的糖蛋白,通过介导细胞与细胞、细胞与细胞外基质间的相互作用参与多种生理及病理过程。细胞黏附分子与包括肝癌在内的多种肿瘤的复发转移有着非常密切的关系。本文就细胞黏附分子在肝癌复发转移中作用的研究进展作一综述。     

Plakophilin3 downregulation leads to a decrease in cell adhesion and promotes metastasis

Plakophilin3 is a desmosomal plaque protein whose levels are reduced in poorly differentiated tumors of the oropharyngeal cavity and in invasive colon carcinomas. To test the hypothesis that plakophilin3 loss stimulates neoplastic progression, plakophilin3 expression was inhibited by DNA vector driven RNA interference in 3 epithelial cell lines, HCT116, HaCaT and fetal buccal mucosa. The plakophilin3-knockdown clones showed a decrease in cell-cell adhesion as assessed in a hanging drop assay, which was accompanied by an increase in cell migration. The HCT116 plakophilin3-knockdown clones showed a decrease in desmosome size as revealed by electron microscopy. These altered desmosomal properties were accompanied by colony formation in soft agar and growth to high density in culture. The HCT116-derived clones showed accelerated tumor formation in nude mice and increased metastasis to the lung, a phenotype consistent with the increased migration observed in vitro and is consistent with data from human tumors that suggests that plakophililn3 is lost in invasive and metastatic tumors. These data indicate that plakophilin3 loss leads to a decrease in cell-cell adhesion leading to the stimulation of neoplastic progression and metastasis.     

Thrombospondin as a mediator of cancer cell adhesion in metastasis

Summary Thrombospondin (TSP) is a 450 kDa adhesive glycoprotein. It is present in high concentrations in the platelet -granule and can readily be secreted following platelet activation where local concentrations can be increased by 3–4 orders of magnitude. TSP is also synthesized by a variety of other cells and is incorporated into their extracellular matrix. TSP is a homotrimer with a number of functional domains, at least four of which might serve as receptor recognizing regions. The amino-terminal heparin binding domain interacts with heparin, other glycosaminoglycans and glycolipids and likely recognizes specific cell surface proteoglycans. The central disulfide cross-linked region, 210 kDa non-reduced and 70 kDa reduced, contains a peptide motif CSVTCG which is apparently responsible for binding to glycoprotein IV (CD36) with high affinity. Immediately adjacent to the calcium binding region of TSP, which undergoes considerable molecular relaxation in the absence of calcium, is an RGDA sequence. TSP has been demonstrated to bind to integrins of the _v3 and _IIb3 class. The carboxy-terminal region of TSP also contains at least one binding epitope for a cell receptor. There are 2 well characterized genes for TSP and truncated forms of TSP have been detected which have inhibitory effects on angiogenesis. Finally, TSP can interact with fibrinogen and fibronectin, perhaps on cellular surfaces, which might serve as secondary receptor-like mechanisms for TSP binding and subsequent mediation of cell adhesion.     

Brain surface invasion and metastasis of murine malignant melanoma variants

Mouse B16 melanoma sublines were selected sequentially for their abilities to colonize brain meninges and leptomeninges of C5713L/6 mice. After 14 selections subline 1316-B14b was established that formed significantly more brain tumor colonies than the parental B16 line. Examination of brains at various times after intravenous or intra-arterial injection of B16 cells by electron microscopy revealed that B14b melanoma cells lodged in small brain blood vessels, proliferated and invaded through vessel walls into brain parenchyma and also along small blood vessels at perivascular sites. Invasion into brain parenchyma was characterized by extension of melanoma cell filopodia resulting in fragmentation and sometimes enfulgment of glial and neural cells.Analysis of cell surface proteins of B16 melanoma sublines revealed increased exposure of a M_r 90 000 glycoprotein on the high brain-colonizing cells. Antibodies against the M_r 90 000 glycoprotein reacted with a variety of human melanoma cell lines and with some fetal and adult tissues, indicating that this melanoma-associated component is not species-, tumor- or tissue-specific. The glycoprotein could be a cell surface receptor important in the survival and growth properties of melanoma cells in brain microenvironments.     

Invadopodia: a new therapeutic target to block cancer metastasis

Cancer cells become dangerous when they acquire the ability to invade through physical barriers in the body and disseminate to distant sites. Recent evidence has demonstrated that cancer cells utilize specialized structures called invadopodia, unique protrusions that concentrate proteases such as matrix metalloproteinases (MMPs), to escape blood vessels during the process of extravasation. Perhaps most exciting is the fact that inhibition of invadopodia through genetic or pharmacological means reduces the ability of cancer cells to extravasate and effectively blocks metastasis. This opens the door for the development of novel therapies targeting invadopodia and cancer metastasis.     

循环肿瘤细胞簇在肿瘤转移中的研究进展

肿瘤转移是肿瘤相关死亡的主要原因,大量研究显示循环肿瘤细胞（circulating tumor cells,CTCs)在肿瘤转移中起着重要作用。越来越多的研究表明循环肿瘤细胞簇（circulating tumor cells clusters,CTC clusters）与单循环肿瘤细胞相比转移能力更强。分离检测技术的不断进步为深入研究循环肿瘤细胞簇提供了便利。本文就循环肿瘤细胞簇在肿瘤转移中的研究进展作一综述。     

Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix

Cancer metastasis poses the greatest challenge to the eradication of malignancy. The majority of clinical and experimental evidence indicates that metastasis is a non-random, organ-specific process. Tumor cell interaction with endothelium and subendothelial matrix constitutes the most crucial factor in determining the organ preference of metastasis. A plethora of cell surface adhesion molecules, which encompass four major families (i.e., integrins, cadherins, immunoglobulins and selectins) and many other unclassified molecules, mediate tumor-host interactions. Adhesion molecules and adhesion processes are involved in most, if not all, of the intermediate steps of the metastatic cascade. Decreased E-cadherin expression and increased CD44 expression are clearly correlated with the acquisition of the invasive capacity of primary tumor cells. Similarly, altered expression pattern of many other adhesion molecules such as upregulated expression of the laminin receptors and depressed expression of fibronectin receptors (51) appears to be involved in tumor cell invasion into the subendothelial matrix. Tumor cell-endothelium interactions involve several well-defined sequential steps that can be analyzed by the Docking and Locking hypothesis at the molecular level. Tumor cell-matrix interactions are determined by the repertoire of adhesion receptors of tumor cells and the unique composition of organ-specific matrices. Our experimental data, together with others', suggest that the integrin IIb3 is one of the major players in these tumor-host interactions. Tumor-host interaction is a dynamic process which is constantly modulated by a host of factors including various cytokines, growth factors and arachidonate metabolites such as 12(S)-HETE. Delineation of the molecular mechanisms of tumor-host interactions may provide additional means to intervene in the metastatic process.     

EFHD1, a novel mitochondrial regulator of tumor metastasis in clear cell renal cell carcinoma

The biological function of many mitochondrial proteins in mechanistic detail has not been well investigated in clear cell renal cell carcinoma (ccRCC). A seven-mitochondrial-gene signature was generated by Lasso regression analysis to improve the prediction of prognosis of patients with ccRCC, using The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium cohort. Among those seven genes, EFHD1 is less studied and its role in the progression of ccRCC remains unknown. The decreased expression of EFHD1 was validated in clinical samples and was correlated with unfavorable outcome. Overexpression of EFHD1 in ccRCC cells resulted in the reduction of mitochondrial Ca²⁺, and the inhibition of cell migration and invasion in vitro and tumor metastasis in vivo. Mechanistically, EFHD1 physically bound to the core mitochondrial calcium transporter (mitochondrial calcium uniporter, MCU) through its N-terminal domain. The interaction between EFHD1 and MCU suppressed the uptake of Ca²⁺ into mitochondria, and deactivated the Hippo/YAP signaling pathway. Further data revealed that the ectopic expression of EFHD1 upregulated STARD13 to enhance the phosphorylation of YAP protein at Ser-127. The knockdown of STARD13 or the overexpression of MCU partly abrogated the EFHD1-mediated induction of phosphorylation of YAP at Ser-127 and suppression of cell migration. Taken together, the newly identified EFHD1–MCU–STARD13 axis participates in the modulation of the Hippo/YAP pathway and serves as a novel regulator in the progression of ccRCC.     

‘Seed and soil’ revisited: mechanisms of site-specific metastasis

Summary Clinical studies have shown that malignant tumors frequently show definite metastatic patterns. This tendency for neoplasms of a particular histologic type to metastasize to a specific organ is also a characteristic of experimental animal tumor systems. Mechanical entrapment, arrest determined by specific recognition between neoplastic cells and capillaries and organ-determined modulation of tumor growth have all been suggested as mechanisms that regulate this specificity. Experimental evidence for the role that each of these mechanisms plays in the regulation of metastatic patterns of transplantable rodent tumors is discussed in this review.     

Brain metastasis from non-seminomatous germ cell tumor of the testis

Brain metastasis occurs rarely in patients with testicular cancer in the modern era where cisplatin-based chemotherapy regimens are used. The occurrence of brain metastasis can be synchronous or metachronous (with or without concurrent systemic disease). Long-term survival can be achieved in some patients. The vast majority of testicular cancer cases with brain metastasis reported in the literature involve nonseminomatous germ cell tumor and this subtype will be the focus of this review. This article reviews the literature of the diagnosis and management of brain metastasis from nonseminomatous germ cell tumor of the testis.     

Lectin binding to cutaneous malignant melanoma: HPA is associated with metastasis formation

Changes in protein glycosylation of tumour cells, as detected by lectin histochemistry, have been associated with metastasis formation in several human malignancies. This study analysed the association between lectin binding and metastasis in cutaneous malignant melanoma. In a 10-year retrospective study, sections of 100 primary cutaneous malignant melanomas were histochemically stained for the following 5 lectins: HPA, SNA-I, MAA, WGA and PHA-L, differing in their carbohydrate specificity. Since differences in the results of HPA binding depending on methodology have been reported, an indirect and a biotinylated method were employed for HPA. Kaplan-Meier analysis of time to first metastasis revealed a positive correlation between HPA binding and metastasis for both methods, with the biotinylated HPA method (P< 0.0001) being superior to the 'indirect' method (P = 0.0006). Cox regression analysis demonstrated that even after adjustment for stage, HPA positivity is an independent predictor for metastasis. The results of the present study indicate that N -acetyl-galactosamine/-glucosamine residues, recognized by HPA, are linked to metastasis in malignant melanoma. In contrast, beta1-6 branched oligosaccharides or sialic acid residues, both of which were correlated with metastasis in other malignancies, are of no functional importance for metastasis formation in malignant melanoma. Thus, HPA proved to be a useful and independent prognostic marker for the metastatic phenotype of melanoma.     

Dickkopf-1相关肿瘤转移研究进展

作为一种分泌型糖蛋白,Dickkopf-1(DKK1)与肿瘤转移关系密切,在肿瘤中高表达或低表达,其异常高表达促进肝癌、胃癌、非小细胞肺癌和乳腺癌等多种恶性肿瘤的转移.最新研究发现,DKK1与肿瘤的潜在转移关系密切.     

Involvement of CD44 and its variant isoforms in membrane-cytoskeleton interaction,cell adhesion and tumor metastasis

Summary CD44s (standard form of CD44) is a transmembrane glycoprotein whose external domain displays extracellular matrix adhesion properties by binding both hyaluronic acid (HA) and collagen. The cytoplasmic domain of CD44s interacts with the cytoskeleton by binding directly to ankyrin. It has been shown that post-translational modifications, such as phosphorylation (by protein kinase C), acylation (by acyl-transferase) and GTP-binding enhance CD44's interaction with cytoskeletal proteins. Most importantly, the interaction between CD44s and the cytoskeletal protein, ankyrin, is required for the modulation of CD44s cell surface expression and its adhesion function.Recently, a number of tumor cells and tissues have been shown to express CD44 variant (CD44v) isoforms. Using RT-PCR and DNA sequence analyses, we have found that unique CD44 splice variant isoforms are expressed in both prostate and breast cancer cell lines and carcinomas. Most importantly, intracellular ankyrin is preferentially accumulated underneath the patched/capped structures of CD44 variant isoform in both breast and prostate cancer cells attached to HA-coated plates. We propose that selective expression of CD44v isoforms unique for certain metastatic carcinomas and their interaction with the cytoskeleton may play a pivotal role in regulating tumor cell behavior during tumor development and metastasis.     

乳腺癌组织LOX蛋白表达与腋窝淋巴结转移相关性分析

目的 赖氨酰氧化酶(lysyl oxidase,LOX)是稳定细胞外基质的关键酶,主要功能是调节细胞黏附、运动及基因转录等.LOX在不同类型肿瘤中可能发挥着不同的作用.本研究通过观察LOX在腋窝淋巴结阳性乳腺癌组织中的表达,分析其与细胞周期蛋白D1 (Cyclin D1)、细胞增殖核抗原(nuclcar-associated antigen,Ki-67)、趋化因子受体4(C-X-C chemokine receptor type 4,CXCR4)及E-钙黏素(E-cadherin)的相关性,探讨LOX在乳腺癌腋窝淋巴结转移中的作用及可能机制.方法 收集广西医科大学附属肿瘤医院2013-09-01-2015-12-31住院手术切除的227例乳腺癌组织及配对的正常乳腺组织(距离癌组织＞5 cm)标本.采用免疫组化法检测LOX蛋白在乳腺癌组织和正常乳腺组织中的表达,分析LOX蛋白表达与临床病理特征及腋窝淋巴结转移数目的关系,以及Cyclin D1、Ki-67、CXCR4和E-cadherin蛋白与LOX蛋白表达的相关性.结果 LOX蛋白在乳腺癌组织中的阳性表达率64.8％ (147/227),显著高于癌旁正常乳腺组织的31.7％(72/227),x2 =49.621,P＜0.001.LOX蛋白表达与乳腺癌组织学分级、原发肿瘤大小、腋窝淋巴结状态、临床分期、ER、PR及HER2状态有关,x2值分别为8.312、6.183、10.597、7.950、19.731、5.221和16.648,P值分别为0.016、0.045、0.014、0.019、＜0.001、0.022和0.001;而与年龄、月经状态、体质量指数和分子分型无明显相关性,均P＞0.05.LOX蛋白表达与腋窝淋巴结转移数目呈正相关,r=0.199,P=0.003.LOX蛋白与Cyclin D1 (r=0.476,P＜0.001)、Ki-67(r=0.492,P＜0.001和CXCR4蛋白(r=0.539,P＜0.001)表达呈中度正相关,与E-cadherin蛋白表达呈中度负相关(r[-0.387,P＜0.001).结论 LOX蛋白在乳腺癌组织中表达升高,并与腋窝淋巴结转移相关.LOX蛋白过表达促进乳腺癌侵袭和转移,并可能通过上调Cyclin D1、Ki-67、CXCR4和下调E-cadherin表达促进腋窝淋巴结的转移.