肿瘤细胞和骨微环境在骨转移中的作用

随着肿瘤治疗水平的提高,肿瘤患者的生存期显著延长,转移性骨肿瘤的发生率呈增长趋势.骨转移引起的剧烈的临床症状和其较长的潜伏期,以及缺乏有效的治疗方法,极大降低了患者的生活质量.本文主要综述了骨转移相关的细胞特征及骨微环境在骨转移中的作用,并分析了影响骨转移形成的相关分子因素,为骨转移的定向分子治疗提供进一步的理论依据.     

Emerging roles of the tumor-associated stroma in promoting tumor metastasis

The stroma in human carcinomas consists of extracellular matrix and various types of non-carcinoma cells, mainly leukocytes, endothelial cells, fibroblasts, myofibroblasts and bone marrow-derived progenitors. The tumor-associated stroma actively supports tumor growth by stimulating neo-angiogenesis, as well as proliferation and invasion of apposed carcinoma cells. It has long been accepted that alterations within carcinoma cells mediate metastasis in a cell-autonomous fashion. Recent studies have, however, suggested an additional notion that cancer cells instigate local and systemic changes in the tumor microenvironment and contribute to niche formation for metastasis. Research, aiming to establish the roles of the tumor-associated stroma in facilitating the spread of carcinoma cells into distant organs, has provided an abundance of data and greater knowledge of the biology of metastatic carcinoma cells and associated stromal cells. This has stimulated further advances in the development of novel therapeutic approaches targeting tumor metastasis.     

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.     

Ketone body utilization drives tumor growth and metastasis

We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm “two-compartment tumor metabolism.” Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes.     

Ketone body utilization drives tumor growth and metastasis

We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm “two-compartment tumor metabolism.” Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes.     

Functional mechanism of Ginsenosides on tumor growth and metastasis

Ginsengs, has long been used as one medicinal herb in China for more than two thousand years. Many studies have shown that ginsengs have preventive and therapeutic roles for cancer, and play a good complementary role in cancer treatment. Ginsenosides, as most important constituents of ginseng, have been extensively investigated and emphasized in cancer chemoprevention and therapeutics. However, the functional mechanism of Ginsenosides on cancer is not well known. This review will focus on introducing the functional mechanisms of ginsenosides and their metabolites, which regulate signaling pathways related with tumor growth and metastasis. Ginsenosides inhibit tumor growth via upregulating tumor apoptosis, inducing tumor cell differentiation and targeting cancer stem cells. In addition, Ginsenosides regulate tumor microenvironment via suppressing tumor angiogenesis-related proteins and pathways. Structural modification of ginsenosides and their administration alone or combinations with other Chinese medicines or chemical medicines have recently been developed to be a new therapeutic strategy for cancer.     

Olfactomedin 4 suppresses tumor growth and metastasis of mouse melanoma cells through downregulation of integrin and MMP genes

Olfactomedin 4 (OLFM4) is highly expressed in gastrointestinal cancers and has an anti-apoptotic function. The roles of OLFM4 in tumor growth and metastasis and how it functions in these processes remain elusive. We investigated the function of OLFM4 in tumor growth and metastasis using B16F10 mouse melanoma cells as an experimental system. Our results showed that OLFM4 had no positive effect on cell viability or cell cycle progression in B16F10 cells. However, it significantly suppressed the tumorigenicity of B16F10 cells, i.e., intradermal primary tumor growth and lung metastasis. OLFM4 also suppressed the migration and invasion of B16F10 cells in vitro. For further insight into the mechanisms underlying OLFM4-mediated suppression of tumor progression, we examined the effect of OLFM4 on the expression of integrin and matrix metalloproteinase (MMP), both of which are involved in tumor progression. Overexpression of OLFM4 clearly reduced the expression levels of integrin α1, integrin α4, integrin α5, integrin α6, and MMP9. Moreover, forced expression of MMP9 attenuated the inhibitory activity of OLFM4 on migration and invasiveness. Our findings provide the experimental evidence that OLFM4 may function as a tumor suppressor and an anti-metastatic gene during tumor progression.     

上皮间质转化在肿瘤侵袭转移中的研究进展

上皮-间质转化（epithelial-mesenchymal transitions,EMT）是上皮细胞向间质细胞转化的现象,不仅参与胚胎发育和正常生理,还参与许多病理过程。同样EMT也参与肿瘤的发生与发展,尤其在促进肿瘤侵袭转移中发挥着重要作用。研究表明,肿瘤细胞借助EMT方式增强肿瘤细胞迁移和运动能力,促进肿瘤的侵袭与转移。在肿瘤侵袭转移历程中,关于EMT发生的分子调控机制研究已取得了良好的进展,但其详细机制仍然不是十分清楚。本文主要介绍生长因子、转录因子、miRNAs、甲基化及其他调控因子在肿瘤EMT中的调控功能,进一步综述EMT在肿瘤侵袭转移中的作用。     

Regulation of invadopodia by the tumor microenvironment

The tumor microenvironment consists of stromal cells, extracellular matrix (ECM), and signaling molecules that communicate with cancer cells. As tumors grow and develop, the tumor microenvironment changes. In addition, the tumor microenvironment is not only influenced by signals from tumor cells, but also stromal components contribute to tumor progression and metastasis by affecting cancer cell function. One of the mechanisms that cancer cells use to invade and metastasize is mediated by actin-rich, proteolytic structures called invadopodia. Here, we discuss how signals from the tumor environment, including growth factors, hypoxia, pH, metabolism, and stromal cell interactions, affect the formation and function of invadopodia to regulate cancer cell invasion and metastasis. Understanding how the tumor microenvironment affects invadopodia biology could aid in the development of effective therapeutics to target cancer cell invasion and metastasis.     

Hyaluronan promotes tumor lymphangiogenesis and intralymphantic tumor growth in xenografts

Hyaluronan （HA）, a high molecular weight glycosaminoglycan in the extracellular matrix, has been implicated in the promotion of malignant phenotypes, including tumor angiogenesis. However, little is known about the effect of HA on tumor-associated lymphangiogenesis. In this study, mouse hepatocellular carcinoma Hca-F cells combined with or without HA were injected subcutaneously into C3H/Hej mice, then angiogenesis and lymphangiogenesis of implanted tumors were examined by immunostaining for plateletendothelial cell adhesion molecule-1 and lymphatic vascular endothelial hyaluronan receptor-1 respectively. Interestingly, we found HA promotes tumor lymphangiogenesis and the occurrence of intratumoral lymphatic vessels, but has little effect on tumor angiogenesis. Moreover, HA also promotes intralymphatic tumor growth, although it is not sufficient to potentiate lymphatic metastasis. These results suggest that HA, which is elevated in most malignant tumor stroma, may also play a role in tumor progression by promoting lymphangiogenesis.     

CD147与肿瘤浸润转移的生物学行为的相互关系

CD147是一种在多种组织细胞膜表面表达的跨膜糖蛋白,通过诱导基质金属蛋白酶(matrix metalloproteinase,M M P)产生,强化胶原蛋白酶水解作用,且可以与整联蛋白(integrin)α3β1和α6β1形成复合体,促进基底膜的降解和肿瘤细胞的移出。另外CD147的过表达促进肿瘤血管内皮生长因子(vascular endothelial growth factor,VEGF)的大量产生,加速肿瘤血管的生成和生长。现在就C D147在肿瘤浸润转移等方面的研究进展作一综述。     

Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis

Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia, with the highest metastasis rate among head and neck cancers. The mechanisms underlying NPC progression remain poorly understood. Genome-wide expression profiling on 18 NPC vs. 18 noncancerous nasopharyngeal tissues together with GeneGo pathway analysis and expression verification in NPC cells and tissues revealed a potential role of urokinase-type plasminogen activator receptor (uPAR) in NPC progression, which has not been investigated in NPC. We then observed that uPAR expression is increased in poorly differentiated, highly metastatic NPC cells compared with lowly metastatic cells or differentiated NPC cells. In vitro studies demonstrated that uPAR regulates NPC cell growth, colony formation, migration, and invasion and promotes the epithelial–mesenchymal transition (EMT). Additional tumor xenograft and spontaneous metastasis experiments revealed that uPAR promotes NPC cell growth and metastasis in vivo. The JAK–STAT pathway is involved in uPAR-regulated signaling in NPC cells as determined by immunoblotting. Moreover, uPAR-mediated growth and motility is partially abolished upon treatment with the Jak1/Jak2 inhibitor INCB018424. We suppressed uPA expression in uPAR-overexpressing NPC cells and found that uPAR-mediated cellular growth and motility is not exclusively dependent on uPA. In summary, uPAR is a significant regulator of NPC progression and could serve as a promising therapeutic target.     

Inflammation and melanoma metastasis

Metastatic melanoma is extremely refractory to existing chemotherapeutic drugs and bioimmune adjuvant therapies, and the life span of patients with metastatic melanoma is often measured in months. Understanding the mechanisms responsible for the development of tumor metastasis is critical for finding successful curative measures. An expending amount of data reveal the importance of inflammatory microenvironment and stroma in cancer initiation and progression, which brings new directions and approaches to cancer treatment. This review will summarize current data on the role of the tumor microenvironment in shaping the metastatic phenotype of melanoma.     

Micrometer-scale oxygen delivery rearranges cells and prevents necrosis in tumor tissue in vitro

Oxygen availability plays a critical role in cancer progression and is correlated with poor prognosis. Despite this connection, the independent effects of oxygen gradients on tumor tissues have not been measured. To address this, we developed an oxygen delivery device that uses microelectrodes to generate oxygen directly underneath three-dimensional tumor cylindroids composed of colon carcinoma cells. The extent of cell death was measured using fluorescence staining. Supplying oxygen for 60 h eliminated the necrotic region typically found in the center of cylindroids despite the continued presence of other nutrient gradients. A mathematical model of cylindroid growth showed that the rate of cell death was more sensitive to oxygen than the growth rate. After oxygenation, a ring of dead cells was observed at the outside edge of cylindroids, and dead cells were observed moving outward from cylindroid centers. This movement suggests that dead cells were pushed by viable cells migrating in response to oxygen gradients, a mechanism that may connect transient oxygen gradients to metastasis formation. These measurements show that oxygen gradients are a primary factor governing cell viability and rearrange cells in tumors.     

Chronotherapy of cancer: periodic perturbations in vascular growth and metastasis

A non-autonomous model was developed for vascular tumor growth and cancer metastasis under periodic perturbations that simulate chronotherapy. It was found that for a critical amplitude and a perturbation frequency of twice the autonomous frequency in vascular growth, less complex and therefore less robust states are reached and the tumor population decreases. In metastasis, similar results were found for a perturbation frequency equal to the autonomous frequency. In metastasis, similar behaviors occur, for a perturbation’s frequency equal to the fundamental frequency of system.     

Application of proteomics in the study of tumor metastasis

Tumor metastasis is the dominant cause of death in cancer patients. However, the molecular and cellular mechanisms underlying tumor metastasis are still elusive.The identification of protein molecules with their expressions correlated to the metastatic process would help to understand the metastatic mechanisms and thus facilitate the development of strategies for the therapeutic interventions and clinical management of cancer. Proteomics is a systematic research approach aiming to provide the global characterization of protein expression and function under given conditions. Proteomic technology has been widely used in biomarker discovery and pathogenetic studies including tumor metastasis. This article provides a brief review of the application of proteomics in identifying molecular factors in tumor metastasis process. The combination of proteomics with other experimental approaches in biochemistry, cell biology, molecular genetics and chemistry, together with the development of new technologies and improvements in existing methodologies will continue to extend its application in studying cancer metastasis.