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

The growth factor Neuregulin‐1 (NRG‐1) regulates myocardial growth and is currently under clinical investigation as a treatment for heart failure. Here, we demonstrate in several in vitro and in vivo models that STAT5b mediates NRG‐1/EBBB4‐stimulated cardiomyocyte growth. Genetic and chemical disruption of the NRG‐1/ERBB4 pathway reduces STAT5b activation and transcription of STAT5b target genes Igf1, Myc, and Cdkn1a in murine cardiomyocytes. Loss of Stat5b also ablates NRG‐1‐induced cardiomyocyte hypertrophy. Dynamin‐2 is shown to control the cell surface localization of ERBB4 and chemical inhibition of Dynamin‐2 downregulates STAT5b activation and cardiomyocyte hypertrophy. In zebrafish embryos, Stat5 is activated during NRG‐1‐induced hyperplastic myocardial growth, and chemical inhibition of the Nrg‐1/Erbb4 pathway or Dynamin‐2 leads to loss of myocardial growth and Stat5 activation. Moreover, CRISPR/Cas9‐mediated knockdown of stat5b results in reduced myocardial growth and cardiac function. Finally, the NRG‐1/ERBB4/STAT5b signaling pathway is differentially regulated at mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to control human subjects, consistent with a role of the NRG‐1/ERBB4/STAT5b pathway in myocardial growth.

STAT5b is a key effector of NRG‐1/ERBB4‐mediated myocardial growth

Amino-terminal truncated forms of Vascular Endothelial Growth Factor-D (VEGF-D) and Vascular Endothelial Growth Factor-C (VEGF-C) which bind to and stimulate Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) but not Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3), and the use of the same in therapeutic applications in which the stimulation of angiogenesis and not lymphangiogenesis is desired.

Vegfr-2-specific forms of vegf-d and vegf-c and uses thereof

The present invention relates to therapeutic methods, uses and compositions comprising CCBE1 and VEGF-C for treating disorders and conditions involving impaired lymphatic system, particularly lymphedema.

Therapeutic use of vegf-c and ccbe1

Cranial lymphatic vessels (LVs) are involved in transport of fluids, macromolecules and CNS immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we reveal an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO-clarified spine segments. Spinal LVs are metameric circuits exiting along spinal nerve roots and connecting to lymph nodes and the thoracic duct. They navigate in the epidural space and the dura mater around the spinal cord, and associate with leukocytes, peripheral dorsal root and sympathetic ganglia. Spinal LVs are VEGF-C-dependent and remodel extensively after spinal cord injury. They constitute an extension to cranial circuits for meningeal fluids, but also a route for perineural fluids and a link with peripheral immune and nervous circuits. Vertebral column LVs may be potential targets to improve the maintenance and repair of 32 spinal tissues as well as gatekeepers of CNS immunity.

Kari Alitalo

Papers

STAT5b is a key effector of NRG‐1/ERBB4‐mediated myocardial growth

Vegfr-2-specific forms of vegf-d and vegf-c and uses thereof

Therapeutic use of vegf-c and ccbe1

Anatomy of the vertebral column lymphatic network in mice

Vascular endothelial growth factors and receptors involved in angiogenesis and lymphangiogenesis