器官因素在恶性肿瘤特异性转移中的意义

器官特异性肿瘤转移涉及肿瘤细胞与宿主器官特性两大因素，即肿瘤细胞在特定器官微血管内滞留、粘附及血管外实质环境的生长三个环节。由Ｐ选择素，Ｅ选择素，ＩＣＡＭ，ＶＣＡＭ 等粘附分子介导的特定器官微血管内皮细胞，与循环中的肿瘤细胞粘附增强，这是决定器官特异性肿瘤转移复杂而重要的环节。亲和器官内皮下基质成分的异质性参与瘤细胞的运动，器官实质细胞通过旁分泌因子调节肿瘤细胞生长、胶原酶表达、血管形成等，在器官特异性肿瘤转移中亦具有重要意义。     

骨桥蛋白与肿瘤转移

骨桥蛋白是一种分泌型、黏附性的糖基化磷蛋白,与其主要受体整合素和CD44相互作用,参与多器官、多组织的生理病理过程,具有多种功能,如介导细胞移行、抑制钙化、调节免疫细胞功能、控制肿瘤细胞表型以及抑制凋亡等。近年来的研究揭示,骨桥蛋白在肿瘤细胞的黏附、移行、浸润、血管新生以及肿瘤的微环境中起关键作用。本文对骨桥蛋白在肿瘤中的信号转导、基因表达与调控以及肿瘤转移过程中的作用予以综述。     

整合素介导血源性转移中肿瘤细胞与宿主细胞相互作用规律研究进展

血源性转移(hematogenous metastasis)是肿瘤细胞转移的重要途径之一。肿瘤细胞的血源性转移是一个复杂的病理学过程,肿瘤细胞进入血液并伴随血液循环而运动,同时通过其表面的整合素分子与血液中的白细胞、血小板等相互作用,或直接与血管内皮细胞发生相互作用,并引发一系列的生物学事件,促进肿瘤细胞的转移。许多生物大分子（如整合素、选择素、趋化因子或细胞因子等）参与并介导肿瘤细胞的黏附与迁移过程,进而形成新的肿瘤转移灶。因此,阐明肿瘤细胞血源性转移对治疗肿瘤的恶性转移、提高癌症患者的寿命有着极其重要的意义。本文综述了整合素在肿瘤细胞血源性转移中的作用及其所涉及的信号转途径,并对其未来研究热点进行展望。整合素在肿瘤血源性转移中作用的深入研究将对临床肿瘤药物靶点的发现和癌症患者的治疗有着重要意义。     

选择素及其配体与肿瘤转移关系的研究进展

肿瘤转移是复杂且多步骤的肿瘤细胞与宿主相互作用的连续过程,包括肿瘤细胞侵袭周围组织、从原发灶脱离进入循环系统、逃避免疫监视以及在远隔器官形成与原发瘤同样类型的转移灶。黏附分子与肿瘤的侵袭、转移密切相关,其中选择素（selectin）家族在肿瘤转移中的作用日益受到人们关注。     

微血管定量与大肠癌转移和预后的关系

肿瘤血管形成在实体瘤的发生、发展、转移及预后中起着重要作用,对指导治疗也有深远的影响。通过对大肠癌组织内微血管的定量计数,发现微血管计数与大肠癌病人的转移和生存率有明显相关性,是一个有价值的独立的预后因素。认为大肠癌组织内微血管的定量计数可反映肿瘤血管生成情况,在判断肿瘤预后,筛选高危复发或转移病人,指导治疗等方面有较大应用价值。本文综述了大肠癌组织内微血管定量的方法、微血管计数与大肠癌转移和预后的关系及意义。     

肿瘤侵袭转移新机制

肿瘤的高侵袭转移能力是多因素的,有原癌基因抑癌基因表达改变、基质金属蛋白酶的表达、血管新生以及黏附分子的作用有关之外,肿瘤细胞的无氧糖酵解途径也赋予肿瘤细胞的高浸润转移潜能。无氧代谢是肿瘤常见的生物学特征,而其中伴随的多种缺氧反应基因的表达尤其是HIF及其相关靶基因的表达也提高了肿瘤组织的转移潜能。关于肿瘤无氧代谢与其侵袭转移能力关系的研究也必将为肿瘤的生物学治疗提供新的思路。     

肿瘤侵袭转移新机制

肿瘤的高侵袭转移能力是多因素的,有原癌基因抑癌基因表达改变、基质金属蛋白酶的表达、血管新生以及黏附分子的作用有关之外,肿瘤细胞的无氧糖酵解途径也赋予肿瘤细胞的高浸润转移潜能。无氧代谢是肿瘤常见的生物学特征,而其中伴随的多种缺氧反应基因的表达尤其是HIF及其相关靶基因的表达也提高了肿瘤组织的转移潜能。关于肿瘤无氧代谢与其侵袭转移能力关系的研究也必将为肿瘤的生物学治疗提供新的思路。     

肿瘤细胞间相互作用:Notch-1信号转导与调控机制

Notch-1信号通路在细胞分化、发育以及增殖、凋亡方面起重要作用,并参与肿瘤的发生发展,与肿瘤的侵袭、运动和转移过程密切相关。活化的Notch-1信号通路能够直接或间接调控细胞的增殖和迁移,促进肿瘤细胞发生上皮细胞间充质转换,并维持其间充质特性,增强肿瘤细胞的黏附能力。同时,Notch信号通路与PI3K/Akt、NF-κB等途径交互作用,将信号级联放大,从而加强调控肿瘤细胞的恶性行为。多种实体瘤中存在异常活化的Notch-1信号通路。从Notch的结构和功能、Notch-1信号通路与肿瘤发生和转移的关系、Notch-1调控肿瘤转移的分子机制与调控网络和以Notch为靶点的肿瘤治疗5个方面进行综述。阐明Notch-1信号通路在肿瘤转移过程中的作用与调控机制以及目前针对Notch-1信号通路的治疗策略,能够为肿瘤的病理机制和临床治疗研究提供参考信息。     

血小板促进肿瘤转移的相关机制研究

肿瘤转移是导致肿瘤患者死亡的主要原因,也是肿瘤难以治疗的关键所在.肿瘤转移过程包括肿瘤细胞穿越肿瘤组织的血管内皮细胞从原发部位迁出、肿瘤细胞随血液运行以及肿瘤细胞在转移部位的植入三个主要环节,转移过程涉及多种细胞黏附分子、细胞外基质以及其他血细胞间的相互作用.研究发现血小板能够促进肿瘤转移,血小板数目增多与肿瘤转移具有正相关性[1-2],而降低血小板数目或者抑制其功能可以明显抑制肿瘤转移[3-4].     

血小板促进肿瘤转移的研究进展

肿瘤转移是导致肿瘤患者死亡的主要原因,也是肿瘤难以治疗的关键所在。肿瘤转移过程包括肿瘤细胞穿越肿瘤组织的血管内皮细胞从原发部位迁出、肿瘤细胞随血液运行以及肿瘤细胞在转移部位的植入三个主要环节,转移过程涉及多种细胞黏附分子、细胞外基质以及其他血细胞间的相互作用。研究发现血小板能够促进肿瘤转移,血小板数目增多与肿瘤转移具有正相关性,而降低血小板数目或者抑制其功能可以明显抑制肿瘤转移。虽然已证实血小板可参与肿瘤转移,但其具体作用机制目前还不十分明确。近年来的研究结果揭示,     

The tumor cell–host organ interface in the early onset of metastatic organ colonisation

Metastatic lesions are the leading cause of death among cancer patients. These lesions usually originate from clonal proliferation of single tumor cells dispersed from the primary tumor into the circulation which finally arrest in the capillary bed of distant organs. The microenvironment within the circulation of potential metastatic target organs provides a variety of pro- and anti- metastatic stimuli regulating the onset of organ colonisation by metastatic tumor cells. Mechanical shear stress, anoikis and cell mediated cytotoxicity within the microcirculation probably clear most circulating tumor cells. Adhesion, and eventually extravasation, are essential initial interactions of circulating tumor cells with distant organs and can provide escape from the cytotoxic environment within the circulation. Adhesion to the capillary wall is mostly controlled by the organ-specific availability of adhesion molecules on tumor cells, the endothelium, and the composition of the underlying extracellular matrix. The availability of pro-adhesive and pro-migratory paracrine signals provided by the organ specific microenvironment can further initiate the onset of metastatic organ colonisation. Tumor cell and microenvironment factors regulating survival within the microcirculation, adhesion and extravasation of tumor cells are highlighted in the review.     

Glycomechanics of the metastatic cascade: tumor cell-endothelial cell interactions in the circulation

Hydrodynamic shear force plays an important role in the leukocyte adhesion cascade that involves the tethering and rolling of cells along the endothelial layer, their firm adhesion or arrest, and their extravasation or escape from the circulatory system by inducing passive deformation, or cell flattening, and microvilli stretching, as well as regulating the expression, distribution, and conformation of adhesion molecules on leukocytes and the endothelial layer. Similarly, the dissemination of circulating tumor cells (CTCs) from the primary tumor sites is believed to involve tethering, rolling, and firm adhesion steps before their eventual extravasation which leads to secondary tumor sites (metastasis). Of particular importance to both the leukocyte adhesion cascade and the extravasation of CTCs, glycoproteins are involved in all three steps (capture, rolling, and firm adhesion) and consist of a variety of important selectin ligands. This review article provides an overview of glycoprotein glycosylation associated with the abnormal glycan expression on cancer cell surfaces, where well-established and novel selectin ligands that are cancer related are discussed. An overview of computational approaches on the effects of fluid mechanical force on glycoprotein mediated cancer cell rolling and adhesion is presented with a highlight of recent flow-based and selectin-mediated cell capturing/enriching devices. Finally, as an important branch of the glycoprotein family, mucins, specifically MUC1, are discussed in the context of their aberrant expression on cancer cells and their role as cancer cell adhesion molecules. Since metastasis relies heavily on glycoprotein interactions in the bloodstream where the fluid shear stress highly regulates cell adhesion forces, it is important to study and understand the glycomechanics of all relevant glycoproteins (well-established and novel) as they relate to the metastatic cascade.     

The metastasis-promoting roles of tumor-associated immune cells

Tumor metastasis is driven not only by the accumulation of intrinsic alterations in malignant cells, but also by the interactions of cancer cells with various stromal cell components of the tumor microenvironment. In particular, inflammation and infiltration of the tumor tissue by host immune cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, have been shown to support tumor growth in addition to invasion and metastasis. Each step of tumor development, from initiation through metastatic spread, is promoted by communication between tumor and immune cells via the secretion of cytokines, growth factors, and proteases that remodel the tumor microenvironment. Invasion and metastasis require neovascularization, breakdown of the basement membrane, and remodeling of the extracellular matrix for tumor cell invasion and extravasation into the blood and lymphatic vessels. The subsequent dissemination of tumor cells to distant organ sites necessitates a treacherous journey through the vasculature, which is fostered by close association with platelets and macrophages. Additionally, the establishment of the pre-metastatic niche and specific metastasis organ tropism is fostered by neutrophils and bone marrow-derived hematopoietic immune progenitor cells and other inflammatory cytokines derived from tumor and immune cells, which alter the local environment of the tissue to promote adhesion of circulating tumor cells. This review focuses on the interactions between tumor cells and immune cells recruited to the tumor microenvironment and examines the factors allowing these cells to promote each stage of metastasis.     

Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential

Adhesive and invasive characteristics appear to be crucial for organ-specific metastasis formation. Using intravital microscopy we investigated the relation between the metastatic potential of colon carcinoma cells and their adhesive and invasive behavior during early steps of metastasis within microvasculatures of rat liver, lung, intestine, skin, muscle, spleen, and kidney in vivo. Colon carcinoma cells with low (HT-29P), intermediate (KM-12C), and high (HT-29LMM, KM-12L4) metastatic potential were injected into nude or Sprague-Dawley rats. Initial interactions with host organ microvasculatures were semiquantitatively analyzed throughout 20 to 30 minutes. Circulating cells passed microvessels in all observed organs without size restriction. All cell lines showed high adhesion rates, independent from their metastatic potential, within liver and lung but very rarely in other organs. Diameters of involved microvessels were larger than diameters of adherent tumor cells. Cell extravasation of highly metastatic HT-29LMM and KM-12L4 cells into liver parenchyma was significantly higher compared to low metastatic cells (P<0.05). Our results indicate that colon carcinoma cells can arrest in target organs without size restriction. Cell adhesion of circulating tumor cells occurred in metastatic target organs only, likely attributable to specific interactions. Migration into target organs correlated with their metastatic potential.     

Organ selectivity in metastasis: regulation by chemokines and their receptors

Cancer metastasis results from a non-random process, in which organ selectivity by the tumor cells is largely determined by factors that are expressed at the remote organs that eventually turn into preferred sites of metastasis formation. These factors support the consecutive steps required for metastasis formation, including tumor cell adhesion to microvessel walls, extravasation into target tissue and migration. Of the different components that regulate organ selectivity, instrumental roles were recently attributed to chemokines and their receptors. The present review presents the rationale standing behind the first studies looking at the potential involvement of chemokine-related components in organ selectivity. Based on these studies and many others that followed, the current paradigm is that chemokines that are expressed at specific organs determine to large extent organ specificity by promoting tumor cell adhesion to microvessel walls, by facilitating processes of extravasation into the target tissue and by inducing tumor cell migration. Moreover, chemokines can possibly support additional steps that are required for "successful" establishment of metastases, such as tumor cell proliferation and survival. The review focuses on the CXCL12-CXCR4 pair as the role model in our current understanding of chemokine involvement in organ selectivity. This review also describes the prominent roles played by CCR7 and its corresponding chemokine ligands (CCL21, CCL19) in lymph node metastasis, and of the CCR10-CCL27 axis in melanoma skin survival and metastasis. Overall, the present discussion describes chemokines as important constituents of the tumor microenvironment at metastatic sites, dictating directionality of chemokine receptor-expressing tumor cells, facilitating their adhesion and extravasation, and eventually contributing to organ selectivity.     

CXCR6: The Role of Environment in Tumor Progression. Challenges for Therapy

The role of chemokines in tumor progression is an essential event that leads to homing and metastasis of tumor cells in a receptor-dependent, organ specific manner. In recent years, the involvement of CXCR6 and its ligand CXCL16 in tumor progression is becoming more evident. Here I review the recent literature on CXCR6/CXCL16. Since CXCR6 was shown recently to be involved in stem cell self renewal and the same cytokine is expressed by a subpopulation of melanoma cells, I discuss new evidences on cancer stem cell theory and the involvement of CXCR6. In particular, in the effort to develop more specific strategies to stop the tumor growth, the present review proposes and discusses the possibility to modulate tumor self renewal affecting asymmetric/symmetric cell division targeting specific factors such as CXCR6.     

Altered melanoma cell surface glycosylation mediates organ specific adhesion and metastasis via lectin receptors on the lung vascular endothelium

Adhesive interactions between the molecules on cancer cells and the target organ are one of the key determinants of the organ specific metastasis. In this communication we show that b1,6 branched N-oligosaccharides which are expressed in a metastasis-dependent manner on B16-melanoma metastatic cell lines, participate in the adhesion process. We demonstrate that high metastatic cells show significantly increased translocation of one of the major carriers of these oligosaccharides, lysosome associated membrane protein (LAMP1), to the cell surface. LAMP1 on high metastatic cells, carry very high levels of these oligosaccharides, which are further substituted with poly N-acetyl lactosamine (polylacNAc), resulting in the expression of high density of very high affinity ligands for galectin-3 on the cell surface. We show that galectin-3 is expressed in highest amount in the lungs as compared to other representative organs. Blocking galectin-3 by pre-incubating the frozen sections of the lungs with 100 mM lactose, substantially inhibited the adhesion of high metastatic cells, while pre-incubation with sucrose had no effect. Finally, by in situ labeling and immunoprecipitation experiment, we demonstrated that the lung vascular endothelial cells express galectin-3 constitutively on their surface. Galectin-3 on the organ endothelium could thus serve as the first anchor for the circulating cancer cells, expressing high density of very high affinity ligands on their surface, and facilitate organ specific metastasis.     

Skeletal Complications of Malignancy V Speaker Abstracts (in order of presentation) S = Speaker

To date, cancer is still the second most prevalent cause of death after cardiovascular diseases in the industrialized word, whereby the primary cause of cancer is not attributed to primary tumor formation, but rather to the growth of metastases at distant organ sites. For several years it was considered that the well-known phenomenon of organ-specific spreading of tumor cells is mostly a mechanical process either directed passively due to size constraints (mechanical trapping theory) or due to a fertile environment provided by the organ in which tumor cells can proliferate (seed and soil hypothesis). Both mechanisms strongly depend on the adhesive properties of tumor cells either to endothelial cells and/or cancer cells, which are facilitated by a variety of cell adhesion molecules including carbohydrates and integrins. Within the past years it became evident that the organ-specific metastatic spreading of tumor cells does not only rely on heterotypic and homotypic adhesive interactions, but also on the interplay of chemokines and their appropriate receptors. Moreover, the identification of cancer stem cells in various tumor tissues has opened new questions. Cancer stem cells possess self-renewal, differentiation, and tumor-initiating capacities. Thus these cells are ideal candidates to be the seed of a secondary tumor. In the present review we will give a brief overview about the complex process of organ-specific metastasis formation depending on the interplay of adhesion molecules, chemokines, and the putative role of cancer stem cells in metastasis formation.     

Interactions between cancer cells and the microvasculature: a rate-regulator for metastasis

Hematogenous metastasis is a major consideration in the staging, treatment and prognosis of patients with cancer. Key events affecting hematogeneous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathologic sequence, specifically: (1) intravasation of cancer cells; (2) the arrest of circulating cancer cells in the microvasculature; (3) cancer cell trauma associated with arrest; (4) microvascular trauma; (5) the inflammatory; and (6) the hemostatic coagulative responses associated with arrest, and finally (7) angiogenesis, leading to tumor vascularization. The evidence shows that through a series of complex interactions with cancer cells, the microvasculature acts as a rate-regulator for the metastatic process, in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli.     

The role of metastasis suppressor genes in metastatic dormancy

Metastasis suppressor genes (MSGs) are defined by their ability to inhibit overt metastasis in a secondary organ without affecting tumor growth at the primary site. Over 20 MSGs have been confirmed in vivo. This class of genes is only unified by their capacity to suppress metastasis, as they encode for proteins with a wide range of biochemical activities that are components of a variety of signaling pathways. In addition, metastasis suppressors impinge upon different stages of the metastatic cascade to manifest their suppressive effects. The MSGs KISS1, KAI1, MKK4/7 and Nm23-H1 promote tumor dormancy at the metastatic site, since tumor cells with induced expression of these MSGs disseminate, but do not form overt metastases in the secondary organ throughout the duration of a metastasis assay. Evidence suggests that KISS1 triggers dormancy in solitary, metastatic tumor cells by causing growth arrest of solitary cells at the secondary site. KAI1 induces growth arrest prior to extravasation by binding a vascular endothelial cell surface marker. MKK4, MKK7 and Nm23-H1 appear to promote dormancy of micrometastatic colonies, after disseminated tumor cells have undergone several rounds of proliferation. Other MSGs may also function in tumor dormancy, but so far their role has not been fully elucidated. Therapeutic approaches that either mimic the effects of MSGs or re-establish MSG expression in metastatic lesions may hold promise for the establishment or maintenance of dormancy.