VEGF у практически здоровых лиц разного возраста.
Оценка фиброгенеза печени по результатам анализа цитокинов.
дна в частности рассказывает о специфике диагностики VEGF мне она показалось любопытной)
" Основной причиной активации ангиогенеза, как при физиологических, так и патологических состояниях,
является недостаток кислорода [4].
Местная гипоксия приводит к экспрессии ряда стимуляторов ангиогенеза, важнейший из которых – фактор роста эндотелия сосудов (Vascularendothelialgrowthfactor, VEGF). Известно, что
VEGF может продуцироваться макрофагами, кератиноцитами, фибробластами, гепатоцитами, эпителиальными, тучными, мезангиальными, эндотелиальными и другими клетками. Он участвует в активации, пролиферации, миграции и дифференцировке эндотелиальных клеток (ЭК), взаимодействуя с ними через специфические тирозинкиназные рецепторы (VEGFR) [5, 6]. Кроме того
, VEGF играет важную роль в инициации процессов воспаления, является одним из наиболее сильных
регуляторов сосудистой проницаемости, обеспечивает привлечение мононуклеаров к месту повреждения, а
также стимулирует их миграцию через эндотелий и функциональную активность [7]."
"Основным фактором, вызывающим повышение уровней VEGF в кровотоке здорового человека с возрастом, является
ишемия, возникающая, по-видимому, в результате нарастания в организме
ряда клинически не выявляемых иммуновоспалительных процессов, приводящих к развитию эндотелиальной дисфункции. Репарация поврежденного эндотелия тесно связана с активацией каскада молекулярно-генетических процессов, порождающих усиление синтеза VEGF
клетками эндотелия и тромбоцитами."
"Низкие концентрации фактора необходимы для продукции NO и простациклина, которые оказывают
антитромботическое действие,
подавляют пролиферацию гладкомышечных клеток и
апоптоз эндотелиальных клеток [21]."
И кто ж там притворился лимфоцитом и макрофагом......?
...............................
Molecular Biology of Cancer
стр. 20 полностью:
...gene(s) is obtained. These can result in chromosomes with regions of DNA that stain uniformly during karyotype analysis of a tumor cell or in the production of extrachromosomal DNA-containing bodies known as double minute chromosomes. A typical example of this type of amplification targets the N-mycgene, which is amplified in 30% of advancedneuroblastomas (54).
More subtle changes at the sequence level affecting growth-controlling genes is also common in human tumors. Mutations can occur as a consequence of either defects in DNA repair or decreased fidelity during DNA replication.
The components of these pathways are critical for maintenance of genome integrity and inherited mutations in the genes of DNA repair proteins and proteins that repair misreplicated DNA explains some inherited cancerprone syndromes (55).
3.7
Angiogenesis
Without the production of new blood vessels ,tumor growth is limited to a volume of a few cubic millimeters by the distance that
oxygen and other nutrients can diffuse through tissues. As tumor size increases, intratumoral O2 levels fall and the center of the mass becomes hypoxic, leading to up-regulation of the hypoxia inducible factor (HIF1). HIF1 is a heterodimeric transcription factor composed of a constitutively expressed HIF-1 beta subunit and an O2 regulatable HIF-1 alpha subunit (56). Under normoxic conditions, levels of HIF1 are kept low through the actions of the VHL tumor suppressor protein, which functions as a ubiquitin ligase that promotes degradation through a proteosome mediated pathway (57).
An important transcriptional target of HIF1 is the VEGF growth factor, which in conjunction with other cytokines, induces neovascularization of tumors and allows them to grow beyond the size limitation imposed by oxygen diffusion. This increased production of proangiogenic factors and reduction of antiangiogenic factors is known as the “angiogenic switch” and is a significant milestone in tumorigenesis that leads to the development of more lethal tumors.
Angiogenesis is the sprouting of capillaries from preexisting vessels during embryonic development and is almost absent in adult tissues with the exception of transient angiogenesis during the female reproductive cycle and wound healing, and the soluble factor that plays a critical role in promoting angiogenesis is vascular endothelial growth factor (VEGF) (58). VEGF was first implicated in angiogenesis when it was identified as a factor secreted by tumor cells, which caused normal blood vessels to become hyperpermeable (59). The following evidence supports a role for VEGF in tumor angiogenesis.
1. VEGF is present in almost every type of human tumor. It is especially high in concentration around tumor blood vessels and in hypoxic regions of the tumor.
2. VEGF receptors are found in blood vessels within or near tumors.
3. Monoclonal neutralizing antibodies for VEGF can suppress the growth of VEGF-expressing solid tumors in mice. These lack any effect in cell culture where angiogenesis is not needed.
Ferrara and Henzel (60) identified VEGF as a growth factor capable of inducing proliferation of endothelial cells but not fibroblasts or epithelial cells. Inhibition of one of the identified VEGF receptors, FLK1, inhibits the growth of a variety of solid tumors (61). Similarly, the injection of an antibody to VEGF strongly suppresses the growth of solid tumors of the subcutaneously implanted human fibrosarcoma cell line HT-1080 (62). There are several forms of VEGF that seem to have different functions in angiogenesis. These isoforms are VEGF, VEGF-B, VEFG-C, and VEGF-D. VEGF-B is found in a variety of normal organs, particularly the heart and skeletal muscle. It can form heterodimers with VEGF and can affect the availability of VEGF for receptor binding (63). VEGF-D seems to be regulated by c-fos and is strongly expressed in the fetal lung (64). However, in the adult it is mainly expressed in skeletal muscle, heart, lung, and intestine. VEGF-D is also able to stimulate endothelial cell proliferation (65). VEGF-C is about 30% homologous to VEGF. Unlike both VEGF and VEGF-B, VEGF-C does not bind to heparin. It is able to...