Tetraspanins and tumor progression

Transmembrane protein tetraspanins either promote or suppress tumor invasion and metastasis. Their effects on tumor progression depend on the multimolecular transmembrane complex called tetraspanin-enriched microdomain (TEM) and are attributed to the alterations in the (1) motogenic and mitogenic behaviors and/or (2) microenvironmental interactions of tumor cells. As the modifiers of cell membrane structure and function, tetraspanins have emerged as diagnostic and prognostic markers and therapeutic targets for tumor progression.     

Transposable elements and tumor progression

Although the concept that transposable elements (TEs) have the potential to enhance their host genomic evolution is widely accepted, it is still generally assumed that TEs primarily owe their prosperity to replicative advantage because the immediate effects on their hosts are generally harmful. To mitigate deleterious impact, hosts employ a cosuppression strategy to tame these perilous elements. The peculiarity of this strategy, however, is that TEs, as targets of suppression, also serve as primary components of this 'TE immune system'. Based on this view, we propose a possible mechanism whereby TEs are involved in tumor progression.     

Genetic aspects in tumor progression

Abstracts of the 4th International Congress of the Metastasis Research Society: Science and Medicine in Cancer MetastasisPlenary Session 4

Genetic aspects in tumor progression     

Phospholipase C-gamma1 in tumor progression

The vast majority of cancer morbidity and mortality arises from tumor progression beyond the primary tumor site. Unfortunately, most therapies are not effective for advanced stage disease with regional extension or distant metastases. Thus, new treatments are needed to target rate limiting steps in tumor progression. The ability of cancers to invade and metastasize requires the acquisition of specific cell behaviors that enable the cell to escape from the localized site, breach the defined boundaries, reach a hospitable ectopic site and grow in this new locale. Recently, dysregulation of cell motility as stimulated by various extracellular factors has gained credence as a rate-limiting alteration in tumor progression in carcinomas and some other solid tumors. This has focused attention on initiators of signaling cascades that regulate tumor migration. In this effort, one molecule, phospholipase C-γ1 (PLCγ), has been shown to function as a key molecular switch. This revised version was published online in July 2006 with corrections to the Cover Date.     

Metalloproteinases in tumor progression. Review

The two biological characteristics that determine the malignancy of cancer are infiltration and metastasis. The study of these mechanisms is related to the invasion of tumoral cells and the relationship of these cells with their stroma, which interact producing the movement and accumulation of inflammatory cells, the formation of new blood vessels, multiplication of fibroblasts and the synthesis of the components of the extra cellular matrix production. Tumoral invasion is conditioned through various enzyme activities, in particular proteases which degrade the matrix, thus facilitating the progression of the tumor. The metalloproteinases (MMP) are a family of proteinases that play an important role in cancer as well as in numerous other diseases. MMP are, therefore, a potential factor in cancer therapy. Several synthetic MMP inhibitors have been developed and have shown successful anti-tumor activity in a variety of animal species, but in clinical studies of patients with advanced forms of cancer, this therapeutic strategy has not resulted as effective. In this article, due to the biological and clinical importance of this therapy, we summarize the current views on the role of metalloproteinases (MMP) in tumor promotion, proliferation, invasion, metastasis and angiogenesis.     

Collagen density promotes mammary tumor initiation and progression

Background

Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood.

Methods

To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen.

Results

Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells.

Conclusion

This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.     

Genetic and epigenetic factors of cervical tumor progression

Infection with high risk papilloma viruses (HPV types 16, 18, and relative ones) initiates the development and progression of uterine neck cancer. The viral genome is found in pre-tumorous lesions (stage I to III intraepithelial neoplasias--CIN) and carcinomas, persisting in cells in episomal or integrated state. In all tumors, there is the expression of two viral transforming genes, E6 and E7, the main function of which is the inactivation of genes that suppress tumoral growth, p53 and retinoblastoma gene. In CIN and carcinomas, losses of heterozygosity are found in various chromosomes, mainly in the areas of suppressor genes; some of them can be specific for certain stages of the malignant process. Among epigenetic alterations, the main significance for the progress of the disease belongs to the methylation of the promoter areas of the genes involved in the process of cell division, which may be specific for each separate tumor and appears in approximately 30 to 40% of tumors. Another important epigenetic alteration is the increase in the expression of p16ink4a gene, which is the inhibitor of cyclin-dependent kinases; this appears at CIN I stage and may serve as an additional early diagnostic marker. Telomerase activity has been identified in all uterine neck tumors, but each tumor has its own spectrum of spliced RNA coding this enzyme. Expression microchip technique has shown that each tumor is individual according to the spectrum of "working" genes, and this spectrum varies in the process of tumor progression.     

Biology of tumor progression in human melanocytes

Tumor progression in the human melanocyte system can be delineated into 6 sequential stages. The first three steps represent nonmalignant melanocyte lesions from focal proliferations of structurally normal melanocytes to lesions with architectural and cytologic atypia. Primary melanoma may be divided into radial growth phase without competence for metastasis and vertical growth phase with metastatic competence. Melanocytes isolated from normal skin, nonmalignant pigmented lesions, and melanomas and maintained in culture have properties that are characteristic for each stage of tumor progression. Cytogenetic studies revealed nonrandom chromosomal abnormalities of advanced melanomas involving chromosomes 1, 6, and 7. Recent progress in tissue culture techniques has allowed studies of growth regulation of normal and malignant cells. Six growth factor receptor-growth factor systems seem to be of biologic significance in the melanocyte system: EGF, NGF, FGF, PDGF, insulin, and beta-TGF. Monoclonal antibodies have characterized a large number of antigens on melanocytes of the various stages of tumor progression, making melanoma one of the most widely studied human tumor systems.     

Exosomes in tumor microenvironment influence cancer progression and metastasis

Exosomes are small membrane vesicles of endocytic origin with a size of 50–100 nm. They can contain microRNAs, mRNAs, DNA fragments, and proteins, which are shuttled from a donor cell to recipient cells. Many different cell types including immune cells, mesenchymal cells, and cancer cells release exosomes. There is emerging evidence that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with tumor environment. Here, we discuss different mechanisms associated with biogenesis, payload, and transport of exosomes. We highlight the functional relevance of exosomes in cancer, as related to tumor microenvironment, tumor immunology, angiogenesis, and metastasis. Exosomes may exert an immunosuppressive function as well as trigger an anti-tumor response by presenting tumor antigens to dendritic cells. Exosomes may serve as cancer biomarkers and aid in the treatment of cancer.     

应激通过肾上腺素能信号影响肿瘤发展进程

<正>越来越多的证据表明慢性心理应激会提高肿瘤的发生率,加剧肿瘤进展^[1]。其它一些躯体应激源例如手术应激、冷应激也被证明会促进肿瘤生长^[2-3]。无论是何种应激源,在机体都会引起一部分与刺激性质无关的非特异性反应,主要由下丘脑-垂体-肾上腺皮质轴(hypothalamic-pituitary-adrenal axis,HPA)和交感神经系统(sympathetic nervous system,SNS)     

CD24与肿瘤侵袭转移的关系

CD24是一种黏蛋白样黏附分子。研究表明,CD24在卵巢癌、乳腺癌、子宫肿瘤、前列腺癌、肺癌等多种肿瘤组织中表达升高。CD24可能通过促进肿瘤细胞的增殖、侵袭和转移参与肿瘤的发生发展。CD24已成为某些恶性肿瘤的侵袭转移标志和预后指标。