Mechanisms of cancer development
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Characteristics of the formation and growth of tumors
For tumor growth, as well as for healthy tissue, it is due to the relation (balance) of cell division and cell death.
- tumor growth is not linear, it depends on the supply of oxygen and nutritients - indirectly on genetic and epigenetic changes that lead to stimulation of tumor angiogenesis and escape of apoptosis and on the interaction with the tumor stroma, which also leads to stimulation of tumor angiogenesis and tumor invasion.
- tumor stem cell – the initial tumor population probably arises from a tissue-specific stem cell or close progenitor cell
Features that a tumor cell needs to acquire for metastasis:
- ability to release the stroma
- angiogenesis – penetration of blood vessels into the tumor and penetration of the tumor into the blood vessels (difference of tumor vessels)
- adhesion ability
- hypoxia tolerance
Regulation of angiogenesis, metastasis
Angiogenesis
- angiogenesis = use/ stimulation of endotelial cells from existing vessels
- vasculoneogenesis = activation of endothelial cell precursors
- can be excessive or insufficient, leading to a number of pathologies (rheumatoid arthritis, blindness, psoriasis, malignant tumors, skleroderma, peptic ulcer disease, sterility)
- activators (growth factors – VEGF, PlGF, FGF, EGF and others) and their receptors and inhibitors (especially statins) and their receptors are used in the regulation of angiogenesis and vasculogenesis
- the expression of mainly proangiogenic factors can be regulated by a number of oncogenes, the expression of mainly antiangiogenic factors can be regulated by tumor suppressor genes
- new vessels formation consists of several steps (disruption of the basement membrane, proliferation, migration, maturation) and both stimulation and inhibition of angiogenesis are used
- tumor vessels do not have a typical structure – a substantial part of the wall can be formed directly by tumor cells (there is a possibility of metastasis)
- the interaction of tumor stromal cells and adjacent tissue (tumor microenviroment) is significantly involved in tumor angiogenesis
- inhibition of angiogenesis (and other cell pathways in general) can occur at several levels:
- growth factor inhibition (antibody)
- receptor acceptor site inhibition (antibody)
- receptor functional domain inhibition (tyrosine kinase inhibitors)
- downstream pathway inhibition
- inhibition of factor-producing factors initial conditions for initiating angiogenesis (inhibition of matrix metalloproteinases)
Metastazování
Nádorová populace je monoklonální, ale heterogenní.
Tvorba metastáz probíhá v několika krocích, pro jejich naplnění musí nádor získat požadované vlastnosti:
- angiogeneze,
- schopnost motility,
- intravazace,
- adheze,
- extravazace,
- angiogeneze ve vzdáleném orgánu.
Selekce rezistentních nádorových klonů
- apoptóza – jak může nádor uniknout apoptóze (jaké mutace jakých genů)? – jak může nádor uniknout hypoxii?
- „multidrug resistence“ – jsou nějaké specifické mutace resp. geny vedoucí k rezistenci nádoru na léčiva?
- terapie – jak můžeme rezistenci ovlivnit? – souvisí s mechanismem vzniku rezistence (cílená terapie, ovlivnění epigenetického pozadí, cílené molekulární vyšetření nádoru)
Odkazy
Zdroje
Kategorie:Patobiochemie
Kategorie:Vnitřní lékařství
Kategorie:Chirurgie
