https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

The hallmarks of cancer.

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

https://science.sciencemag.org/content/sci/235/4785/177.full.pdf

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Disclosed herein are various uses for VEGF-D polypeptides. Exemplary uses include methods of stimulating endothelial cell proliferation, methods of stimulating vascular permeability, methods of stimulating angiogenesis and methods of activating VEGFR-2 and VEGFR-3 using VEGF-D polypeptides.

Methods of making VEGF-D polypeptides


 The apelin/apela – apelin receptor system regulates a variety of physiological cardiovascular functions including vascular tone, cardiac contractility, angiogenesis, and energy metabolism. However, the cell type specific effects of apelin/apela in the cardiovascular system are not well understood. The aim of this study was to investigate the potential role of apelin and apela in regulating development of myocardial fibrosis and to identify the signaling mechanisms underlying the anti-fibrotic effects. To investigate the role of apelin and apela
 in vivo
 , 2-month-old C57BL/6N male mice were injected with AAV9.LacZ, AAV9.Apelin or AAV9.Apela and subjected to thoracic aortic constriction (TAC) for 6 weeks. Echocardiography analysis at the end of the study showed that overexpression of either apelin or apela attenuated TAC-induced left ventricular (LV) dysfunction and increase in LV mass. Analysis of cardiac tissue showed downregulation of collagen I and fibrosis related periostin mRNA expression levels and reduced accumulation of interstitial fibrosis in the left ventricles of mice overexpressing apelin or apela. Studies in human cardiac fibroblasts
 in vitro
 showed that apelin and apela attenuate TGFβ1-induced collagen expression and secretion. Analyses of LV tissue and human fibroblast samples indicated that apelin and apela regulate the stress-induced activation of MAPK pathways. Chemical inhibitors and genetic modification of specific signaling elements identified p38 MAPK as a central signaling pathway mediating the inhibitory effect of apelin and apela on TGFβ1 signaling and TGFβ1-induced collagen production. In summary, we show that apelin and apela attenuate hemodynamic pressure overload -induced LV dysfunction and myocardial fibrosis and identify a novel signaling mechanism regulating the response. Our data suggests that activation of apelinergic signaling could offer a novel therapeutic approach to prevent the development of cardiac fibrosis and heart failure.


Abstract 13155: Apelin and Apela for Therapy of Myocardial Fibrosis and Heart Failure

The chapter describes the Tie that is a receptor protein-tyrosine kinase of unknown function. Tie is a monomer that contains 1138 amino acids. A cDNA lacking the first EGF domain has been observed. Tie contains hydrophobic signal and transmembrane sequences. The intracellular tyrosine kinase domain is split by a 14-amino acid kinase insert and followed by a 32-amino-acid C-terminal tail. TIE mRNA has been cloned and sequenced from human erythroleukemia cells and from mouse and bovine sources also. Expressed by endothelial cells, megakaryoblasts, and mouse hematopoietic stem cells, TIE mRNA is enhanced during angiogenesis.

Tie: Tie protein-tyrosine kinase (vertebrates)

VEGF-D, a new member of the PDGF family of growth factors, which among other things stimulates endothelial cell proliferation and angiogenesis and increases vascular permeability, as well as nucleotide sequences encoding it, methods for producing it, antibodies and other antagonists to it, transfected or transformed host cells for expressing it, pharmaceutical compositions containing it, and uses thereof in medical and diagnostic applications.

Kari Alitalo

Papers

Methods of making VEGF-D polypeptides

Abstract 13155: Apelin and Apela for Therapy of Myocardial Fibrosis and Heart Failure

Tie: Tie protein-tyrosine kinase (vertebrates)

VEGF-D polynucleotides and methods of use