Tumor metastasis is the main cause of cancer‐related death. Understanding the molecular mechanisms underlying tumor metastasis is crucial to control this fatal disease. Several molecular pathways ...orchestrate the complex biological cell events during a metastatic cascade. It is now well known that bidirectional interaction between tumor cells and their microenvironment, including tumor stroma, is important for tumor progression and metastasis. Tumor stromal cells, which acquire their specific characteristics in the tumor microenvironment, accelerate tumor malignancy. The formation of new blood vessels, termed as tumor angiogenesis, is a requirement for tumor progression. Tumor blood vessels supply nutrients and oxygen and also provide the route for metastasis. Tumor endothelial cells, which line tumor blood vessels, also exhibit several altered phenotypes compared with those of their normal counterparts. Recent studies have emphasized “angiocrine factors” that are released from tumor endothelial cells and promote tumor progression. During intravasation, tumor cells physically contact tumor endothelial cells and interact with them by juxtacrine and paracrine signaling. Recently, we observed that in highly metastatic tumors, tumor endothelial cells interact with tumor cells by secretion of a small leucine‐rich repeat proteoglycan known as biglycan. Biglycan from tumor endothelial cells stimulates the tumor cells to metastasize. In the present review, we highlight the role of tumor stromal cells, particularly endothelial cells, in the initial steps of tumor metastasis.
We here summarize the current reports pertaining to tumor stromal cells in the tumor microenvironment. Furthermore, we highlight the role of TECs in promoting tumor metastasis.
Tumor progression depends on the process of angiogenesis, which is the formation of new blood vessels. These newly formed blood vessels supply oxygen and nutrients to the tumor, supporting its ...progression and providing a gateway for tumor metastasis. Tumor angiogenesis is regulated by the balance between angiogenic activators and inhibitors within the tumor microenvironment. Because the newly formed tumor blood vessels originate from preexisting normal vessels, tumor blood vessels, and tumor endothelial cells (TECs) have historically been considered to be the same as normal blood vessels and endothelial cells; however, evidence of TECs' distinctive abnormal phenotypes has increased. In addition, it has been revealed that TECs constitute a heterogeneous population. Thus, TECs that line tumor blood vessels are important targets in cancer therapy. We have previously reported that TECs induce cancer metastasis. In this review, we describe recent studies on TEC abnormalities related to cancer progression to provide insight into new anticancer therapies.
Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from their normal counterparts, for example, by changes in morphology. An ...important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, even though these endothelial cells are structurally and functionally abnormal. To date, many anti‐angiogenic drugs have been developed, but, their therapeutic efficacy is not dramatic and they have also been reported to cause toxic side effects. To develop ideal antiangiogenic therapies, understanding tumor endothelial cell abnormalities is important. We have isolated tumor endothelial cells from mouse tumor xenografts and have shown that tumor‐associated endothelial cells are abnormal. Tumor‐associated endothelial cells upregulate many genes, such as epidermal growth factor receptor (EGFR). Tumor‐associated endothelial cells are also more sensitive to EGF. They also have relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells are cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid. They had normal centrosomes and remained cytogenetically stable in culture even up to 20 passages. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment. Questions as to whether or not tumor endothelial cells become resistant to antiangiogenic drugs are thus raised. Our preliminary data show that tumor endothelial cells are more resistant to certain chemotherapeutic drugs. Studies to evaluate the mechanism for cytogenetic abnormalities in tumor endothelial cells are underway. It is becoming quite clear that the tumor vasculature is much more complex and unpredictable than initially perceived. Here, we provide an overview of the current studies on tumor endothelial cell abnormalities. (Cancer Sci 2008; 99: 459–466)
Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular ...barrier and contribute to hematogenous metastasis; however, the role of oral bacteria‐induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expression of molecules associated with vascular inflammation and barrier‐associated adhesion was analyzed. Tumor metastasis was evaluated after intravenous injection of S. mutans in murine breast cancer hematogenous metastasis model. The results indicated that S. mutans invaded the ECs accompanied by inflammation and NF‐κB activation. S. mutans exposure potentially disrupts endothelial integrity by decreasing vascular endothelial (VE)‐cadherin expression. The migration and adhesion of tumor cells were enhanced in S. mutans‐stimulated ECs. Furthermore, S. mutans‐induced lung vascular inflammation promoted breast cancer cell metastasis to the lungs in vivo. The results indicate that oral bacteria promote tumor metastasis through vascular inflammation and the disruption of vascular barrier function. Improving oral hygiene in patients with cancer is of great significance in preventing postoperative pneumonia and tumor metastasis.
The oral bacterium, Streptococcus mutans (S. mutans) invades endothelial cells (ECs) accompanied by inflammation. S.mutans disrupts endothelial integrity and subsequently promotes tumor cell extravasation and finally promotes breast cancer cell metastasis to the lungs.
Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to ...traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.
The objective of this study was to develop an efficient dual-ligand based PEGylated liposomal delivery system that had target specificity as well as properties that would enhance cellular uptake. ...PEGylated liposomes (PEG-LP) were prepared by the lipid film hydration method by adding distearoyl phosphoethanolamine-polyethylene-glycol-2000 conjugate (DSPE-PEG2000) to a lipid mixture. The cyclic RGD (Arg-Gly-Asp) peptide, a specific ligand with affinity for Integrin α
vβ
3 was coupled to the distal end of the PEG on the PEG-LP (RGD-PEG-LP). Stearylated octaarginine (STR-R8) was incorporated on the surface of the RGD-PEG-LP as dual-ligand (R8/RGD-PEG-LP) that functions as a cell penetrating peptide (CPP). RGD-PEG-LP and R8/RGD-PEG-LP were preferentially taken up by caveolae-mediated and clathrin-mediated endocytosis pathways, respectively. Compared to PEG-LP, R8/RGD-PEG-LP showed an enhanced cellular uptake as well as a higher transfection efficiency in Integrin α
vβ
3 expressing cells. However, the amount of cellular uptake or gene expression by the single ligand versions was negligible, even in Integrin α
vβ
3 expressing cells. No remarkable difference in cellular uptake or gene expression was observed for cells in which the expression of targeted receptors was absent. It can be concluded that dual-ligand modified PEG-LP possesses a strong capability for the efficient internalization of PEG-LP and consequently would be an effective tool for the targeted delivery of macromolecules or chemotherapeutics through accelerated cellular uptake.
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Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential ...for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the inner surfaces of tumor blood vessels reportedly show phenotypes distinct from those of their normal counterparts. As examples, TECs show cytogenetic abnormalities, resistance to anticancer drugs, activated proliferation and migration, and specific gene expression patterns. TECs contain stem-like cell populations, which means that the origin of TECs is heterogeneous. In addition, since some abnormal phenotypes in TECs are induced by factors in the tumor microenvironment, such as hypoxia and tumor cell-derived factors, phenotypic diversity in TECs may be caused in part by intratumoral heterogeneity. Recent studies have identified that the interaction of tumor cells and TECs by juxtacrine and paracrine signaling contributes to tumor malignancy. Understanding TEC abnormality and heterogeneity is important for treatment of cancers. This review provides an overview of the diversity of TECs and discusses the interaction between TECs and tumor cells in the tumor microenvironment.
Heterogeneity of tumor endothelial cells Hida, Kyoko; Ohga, Noritaka; Akiyama, Kosuke ...
Cancer science,
November 2013, Letnik:
104, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Tumor blood vessels play important roles in tumor progression and metastasis. Thus, targeting tumor blood vessels is an important strategy for cancer therapy. Tumor endothelial cells (TECs) are the ...main targets of anti‐angiogenic therapy. Although tumor blood vessels generally sprout from pre‐existing vessels and have been thought to be genetically normal, they display a markedly abnormal phenotype, including morphological changes. The degree of angiogenesis is determined by the balance between the positive and negative regulating molecules that are released by tumor and host cells in the microenvironment. Reportedly, tumor blood vessels are heterogeneous with TECs differing from normal endothelial cells (in contrast to the conventional view). We recently compared characteristics of different TECs isolated from highly and low metastatic tumors. We found TECs from highly metastatic tumors had more proangiogenic phenotypes than those from low metastatic tumors. Elucidating the variety of TEC phenotypes and identifying TEC molecular signatures should lead to more complete understanding of the mechanisms of tumor progression, discovery of new therapeutic targets, and development of biomarkers. This review considers current studies on TEC heterogeneity and discusses the therapeutic implications of these findings.
Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that ...biglycan, a small leucine‐rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC‐derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope‐type nanodevice (MEND), which contains a unique pH‐sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg–Gly–Asp–D–Phe–Lys) (cRGD) into MEND because αVβ3 integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD‐MEND‐encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS‐RC‐2 tumor‐derived TECs and induced in vitro RNAi‐mediated gene silencing. MEND was then injected intravenously into OS‐RC‐2 tumor‐bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT‐PCR indicated that biglycan was knocked down by biglycan siRNA‐containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA‐containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment.
Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. In this study, we targeted biglycan in TECs using an in vivo siRNA delivery system known as a multifunctional envelope‐type nanodevice (MEND). We report, for the first time, that TEC‐specific marker inhibition using an in vivo siRNA delivery system can cause therapeutic effects in tumors.
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