Perspectives on lymphangiogenesis and angiogenesis in cancer

Tumor-associated neovascularization allows tumor cells to express their critical growth advantage, whereas lymphatic invasion is crucial for the metastatic process. Various growth factors stimulate blood and lymphatic neovascularization and modulate vessel permeability in tumors. The first anti-angiogenic drugs are already in routine use, and new anti-vascular therapeutics are evaluated in clinical trials. Conversely, pro-lymphangiogenic therapy could be implemented to treat cancer survivors suffering from secondary lymphedema.     

Integrins in angiogenesis and lymphangiogenesis

Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.     

Mouse models for cancer research

Mouse models of cancer enable researchers to learn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Journal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the de...     

Interleukin-18 suppresses angiogenesis and lymphangiogenesis in implanted Lewis lung cancer

Objective  

To investigate the effects of interleukin-18 (IL-18) on implanted Lewis lung cancer in suppressing angiogenesis and lymphangiogenesis.     

Mouse models for lung cancer

Lung cancer is a devastating disease and a major therapeutic burden with poor survival rates. It is responsible for 30% of all cancer deaths. Lung cancer is strongly associated with smoking, although some subtypes are also seen in non-smokers. Tumors in the latter group are mostly adenocarcinomas with many carrying mutations in the epidermal growth factor receptor (EGFR). Survival statistics of lung cancer are grim because of its late detection and frequent local and distal metastases. Although DNA sequence information from tumors has revealed a number of frequently occurring mutations, affecting well-known tumor suppressor genes and proto-oncogenes, many of the driver mutations remain ill defined. This is likely due to the involvement of numerous rather infrequently occurring driver mutations that are difficult to distinguish from the very large number of passenger mutations detected in smoking-related lung cancers. Therefore, experimental model systems are indispensable to validate putative driver lesions and to gain insight into their mechanisms of action. Whereas a large fraction of these analyzes can be performed in cell cultures in vitro, in many cases the consequences of the mutations have to be assessed in the context of an intact organism, as this is the context in which the Mendelian selection process of the tumorigenic process took place and the advantages of particular mutations become apparent. Current mouse models for cancer are very suitable for this as they permit mimicking many of the salient features of human tumors. The capacity to swiftly re-engineer complex sets of lesions found in human tumors in mice enables us to assess the contribution of defined combinations of lesions to distinct tumor characteristics such as metastatic behavior and response to therapy. In this review we will describe mouse models of lung cancer and how they are used to better understand the disease and how they are exploited to develop better intervention strategies.     

Mouse models for liver cancer

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer is the third leading cause of cancer-related cell death in human and the fifth in women worldwide. The incidence of HCC is increasing despite progress in identifying risk factors, understanding disease etiology and developing anti-viral strategies. Therapeutic options are limited and survival after diagnosis is poor. Therefore, better preventive, diagnostic and therapeutic tools are urgently needed, in particular given the increased contribution from systemic metabolic disease to HCC incidence worldwide. In the last three decades, technological advances have facilitated the generation of genetically engineered mouse models (GEMMs) to mimic the alterations frequently observed in human cancers or to conduct intervention studies and assess the relevance of candidate gene networks in tumor establishment, progression and maintenance. Because these studies allow molecular and cellular manipulations impossible to perform in patients, GEMMs have improved our understanding of this complex disease and represent a source of great potential for mechanism-based therapy development. In this review, we provide an overview of the current state of HCC modeling in the mouse, highlighting successes, current challenges and future opportunities.     

Mouse models for colorectal cancer

Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with the number of affected people increasing. There are many risk factors that increase CRC risk, including family or personal history of CRC, smoking, consumption of red meat, obesity, and alcohol consumption. Conversely, increased screening, maintaining healthy body weight, not smoking, and limiting intake of red meat are all associated with reduced CRC morbidity and mortality. Mouse models of CRC were first used in 1928 and have played an important role in understanding CRC biology and treatment and have long been instrumental in clarifying the pathobiology of CRC formation and inhibition. This review focuses on advancements in modeling CRC in mice.     

国产虫草素对HeLa细胞凋亡及细胞周期影响的实验研究

目的 观察重组人血管内皮抑制素注射液(商品名恩度 )对宫颈癌裸鼠移植瘤生长、转移及血管、淋巴管生成的抑制作用.方法 以人宫颈癌HeLa细胞株接种BALB/c-nu雌性裸鼠,建立动物模型.随机将裸鼠分为对照组、顺铂组、恩度组、小剂最恩度(10 ms/kg)+顺铂组和大剂量恩度(20 mg/kg)+顺铂组等5组,观察肿瘤生长和淋巴结转移情况.采用免疫组织化学法检测移植瘤的微血管密度(MVD)和微淋巴管密度(MLD).结果 大剂量恩度+顺铂组、小剂量恩度+顺铂组和恩度组的肿瘤生长速度明显慢于对照组和顺铂组(P<0.05).大剂量恩度+顺铂组、小剂量恩度+顺铂组、恩度组、顺铂组和对照组的裸鼠肿瘤淋巴结转移率分别为0(0/8)、12.5%(1/8)、12.5%(1/8)、62.5%(5/8)、75.0%(6/8,P=0.002).大剂量恩度+顺铂组、小剂量恩度+顺铂组、恩度组、顺铂组和对照组的裸鼠肿瘤MVD分别为10.88±1.38、10.25±1.22、10.83±2.29、15.58±2.31和22.08±1.93(P=0.000),MLD分别为5.00±0.63、5.17±0.75、6.00±0.63、14.33±1.63和13.67±1.21(P=0.000).结论 恩度可以通过抑制裸鼠宫颈癌模型的血管和淋巴管生成,而抑制肿瘤的生长和淋巴结转移.     

Mouse models for colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in the Western world. Much has been learned about colorectal cancer from human inherited syndromes, such as familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). Mouse models for CRC were generated by introducing mutations into the mouse genes, whose human counterparts were implicated in the onset and progression of CRC. Central among these are mice carrying mutations in the Adenomatous polyposis coli (Apc) gene. Although most of these Apc mutations share some common phenotypes as homozygous embryonic lethality and tumor predisposition, the severity of the tumor predisposition is variable. Mice with mutations in the mismatch repair genes, Msh2 and Mlh1, exhibit a mismatch repair defect and are predisposed to developing gastrointestinal cancer, lymphomas and tumors of other organ systems. Mice carrying a mutation in the Pms2 gene are predisposed to lymphomas and other tumors. Mice with a mutation in the Msh6 gene have a defect in base mismatch repair and show a tumor predisposition phenotype. Mice with mutations in Mlh1, Pms2 and Msh5 have defects in meiosis suggesting unique roles for these genes in gametogenesis.     

The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients

BackgroundAngiogenesis and lymphangiogenesis have been reported to affect malignant phenotype.MethodWe investigated 147 patients with non-small cell lung cancer (NSCLC). Immunohistochemistry using D2-40 was performed to evaluate lymphatic vessel density (LVD), including Micro-LVD (without lumen), Tubal-LVD (with lumen) and lymphatic vessel invasion (LVI). The intratumoural microvessel density (MVD) was evaluated by CD-34 immunostaining. The expressions of vascular endothelial growth factor-A (VEGF-A) and VEGF-C were also studied.ResultsLymphangiogenesis was significantly associated with Micro-LVD (p = 0.0003). The VEGF-C expression was significantly associated with the Micro-LVD (p = 0.0057). In contrast, the VEGF-A expression was significantly associated with the MVD (p = 0.0092). The survival was significantly lower in patients with Micro-LVD-high tumours than in patients with Micro-LVD-low tumours (p = 0.0397). Survival was also significantly lower in patients with MVD-high tumours than in patients with MVD-low tumours (p = 0.0334). A multivariate analysis demonstrated that the Micro-LVD (p = 0.0363) and the MVD (p = 0.0232) were independent prognostic factors for NSCLC patients.ConclusionsLymphangiogenesis, specifically Micro-LVD and angiogenesis are independently associated with a poor prognosis in NSCLC patients.     

Mouse models in oncogenesis and cancer therapy

Animal models have been critical in the study of the molecular mechanisms of cancer and in the development of new antitumor agents; nevertheless, there is still much room for improvement. The relevance of each particular model depends on how close it replicates the histology, physiological effects, biochemical pathways and metastatic pattern observed in the same human tumor type. Metastases are especially important because they are the main determinants of the clinical course of the disease and patient survival, and are the target of systemic therapy. The generation of clinically relevant models using the mouse requires their humanization, since differences exist in transformation and oncogenesis between human and mouse. Although genetically modified (GM) mice have been instrumental in understanding the molecular mechanisms involved in tumor initiation, they have been less successful in replicating advanced cancer. Moreover, a particular genetic alteration frequently leads to different tumor types in human and mouse and to lower metastastatic rates in GM mice than in humans. These findings question the capacity of current GM mouse carcinoma models to predict clinical response to therapy. On the other hand, orthotopic (ORT) xenografts of human tumors, or tumor cell lines, in nude mice reproduced the histology and metastatic pattern of most human tumors at advanced stage. Usingex vivo genetic manipulation of human tumor cells, ORT models can be used to molecularly dissect the metastatic process and to evaluatein vivo tumor response to therapy, using non-invasive procedures. Nevertheless, this approach is not useful in the study of the initial stages of tumorigenesis or the contribution of the immune system in this process. Despite ORT models are more promising than the most commonly used subcutaneous xenografts in preclinical drug development, their capacity to predict clinical response to antitumor agents remains to be studied. Humanizing mouse models of cancer will most likely require the combined use of currently available methodologies. Supported by an unrestricted educational grant from AstraZeneca.     

胃癌组织中微血管、微淋巴管生成和增殖细胞分布与胃癌预后的关系

Objective  

We investigated the relationship between lymphangiogenesis, angiogenesis and cell proliferation in gastric cancer.     

A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis

We have recently gained a remarkable understanding of the mutational landscape of head and neck squamous cell carcinoma (HNSCC). However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still poorly defined. Here, we have focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (JNK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB203580; a retro-inhibition strategy consisting in the use of SB203580 combined with the expression of an inhibitor-insensitive mutant form of p38α; and short-hairpin RNAs (shRNAs) targeting p38α. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38α functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis.     

Mouse models of colorectal cancer

Colorectal cancer is one of the most common malignancies in the world. Many mouse models have been developed to evaluate features of colorectal cancer in humans. These can be grouped into genetically-engineered, chemically-induced, and inoculated models. However, none recapitulates all of the characteristics of human colorectal cancer. It is critical to use a specific mouse model to address a particular research question. Here, we review commonly used mouse models for human colorectal cancer.