Komplexita interakcií nádorového procesu

The complexity of interactions of the tumour growth process

It was believed for rather a long time that the only components of tumour tissue are transformed cells characterised by hyper‑proliferation, invasivity and immortalisation. Therapeutic strategies thus focused on autonomous proliferation and tumour cell survival. These result from oncogene activation and inactivation of tumour‑suppressor genes. Research studies showed that tumour growth itself is a complex process. In addition, studies confirmed involvement of heterotypical multicellular interactions in tumour tissue. Complexity as a characteristic is one of the processes that do not demonstrate attributes of linear systems. The process of tumour growth involves certain patterns that cannot be classified according to duration and sequence. Consequently, tumour growth can be viewed as a process with features typical for complexity. From this perspective, tumour environment consists of a range of cells, such as endothelial cells and their progenitor cells, pericytes, fibroblasts, tumour‑associated fibroblasts, myofibroblasts, smooth muscle cells, mast cells, T‑ and B‑lymphocytes, neutrophils, eosinophils, basophils, NK‑cells and several different forms of macrophages. At present, well‑founded assumptions exist that in‑depth study of intra‑tumour environment might lead to formulation of new principles in tumour biology as well as introduction of new therapeutic strategies. Research into details of tumour microenvironment is needed to expand scientific knowledge as well as to, subsequently, define tumour biomarkers. Monitoring of these biomarkers will facilitate molecular diagnostics. Biomarkers will be widely used to monitor tumour growth as well as to monitor the process of treatment. Monitoring of combinations of biomarkers will enable more detailed characterisation of tumour microenvironment. These might include, apart from receptors, signal molecules, growth factors and molecules accelerating apoptosis, specific molecules as well as their combinations or neoangiogenesis or tumour innervation parameters. Tumour complexity involves not just intracellular environment but also intracellular relationships and associations between cells and extracellular tumour components. Detection of circulating tumour cells represents another parameter to be monitored. Low‑molecular weight fluorescent dyes will very likely be used for their detection. It can be assumed that circulating tumour cells will be used as markers of prognosis as well as indicators of malignity progression and treatment. Scientific advances in this area will facilitate individualised therapy of patients suffering from cancers. The aim of the present review study was to analyze scientific knowledge from the perspective of acceptance of complexity and heterogeneity of each tumour. We perceived processing of the vast amounts of literature as meaningful with respect to recognition of new knowledge and theoretical preparation for expected changes in diagnostics and treatment of tumours. We believe that the presented findings are a useful step towards achievement of comprehensive insight into tumour microenvironment.

Key words:
angiogenesis – tumour innervation – tumour microenvironment – vagus nerve – anti‑inflammatory effects of nervous system

Autori: Z. Valášková ¹; S. Kiňová ²; Ľudovít Danihel ³; I. Ďuriš ²; D. Markovičová ¹; B. Mravec ^1,4; I. Hulín ¹
Pôsobisko autorov: Oddelenie klinickej patofyziológie Ústavu patologickej fyziológie Lekárskej fakulty UK Bratislava, Slovenská republika, prednosta doc. MU Dr. Marián Bernadič, CSc., mim. prof. ¹; I. interná klinika Lekárskej fakulty UK a FN Bratislava, Slovenská republika, prednostka doc. MU Dr. Soňa Kiňová, PhD. ²; Ústav patologickej anatómie Lekárskej fakulty UK Bratislava, Slovenská republika, prednosta prof. MU Dr. Ľudovít Danihel, CSc. ³; Ústav experimentálnej endokrinológie SAV Bratislava, Slovenská republika, riaditeľ prof. MU Dr. Iwar Klimeš, DrSc. ⁴
Vyšlo v časopise: Vnitř Lék 2009; 55(12): 1145-1158
Kategória: Reviews

Súhrn

Pomerne dlho pretrvávali predstavy, že nádor je tvorený iba transformovanými bunkami, pre ktoré je typická hyperproliferácia, invazívnosť a imortalizácia buniek. Terapeutické stratégie boli preto zamerané na autonómnu proliferáciu a prežívanie nádorových buniek. Ide o vlastnosti podmienené aktiváciou onkogénov a inaktiváciou tumor‑supresorových génov. Vedecké sledovania priniesli poznanie, že samotný rast nádoru je komplexným dejom. Okrem toho potvrdili účasť heterotypických multicelulárnych interakcií v nádorovom tkanive. Komplexita ako charakteristika sa priraďuje k tým dejom, ktoré nevykazujú vlastnosti lineárnych systémov. V priebehu nádorového rastu sú určité zákonitosti, ktoré nie je možné presne usporiadať z hľadiska trvania a následnosti. Preto ho môžeme považovať za dej so znakmi komplexity. Pri takomto pohľade nádorové prostredie tvoria viaceré druhy buniek, ako sú endotelové bunky a ich progenitorové bunky, pericyty, fibroblasty, fibroblasty asociované s nádorom, myofibroblasty, hladkosvalové bunky, žírne bunky, T‑ a B‑lymfocyty, neutrofily, eozinofily, bazofily, NK‑bunky a niekoľko foriem makrofágov. V súčasnosti sa opodstatnene predpokladá, že hlboké štúdium vnútorného prostredia nádorov môže viesť k formovaniu nových základov nádorovej biológie ako aj terapeutických postupov. Štúdium detailov mikroprostredia nádorov je potrebné z hľadiska vedeckého poznania a následne aj pre definovanie biomarkerov charakterizujúcich nádory. Ich sledovanie prehĺbi molekulovú diagnostiku. Biomarkery sa budú využívať v širokom meradle pre monitorovanie priebehu rastu nádorov a aj priebehu liečby. Sledovanie kombinácie biomarkerov umožní bližšie charakterizovať mikroprostredie nádorov. Okrem receptorov, signálnych molekúl, rastových faktorov, molekúl akcelerujúcich apoptózu to môžu byť nielen molekuly samotné, ale aj ich kombinácie, alebo charakteristiky neoangiogenézy, alebo inervácie nádorov. Komplexita nádorov zahrňuje nielen intracelulárne prostredie, ale aj intercelulárne vzťahy a vzťahy buniek s extracelulárnymi súčasťami nádorov. K doteraz známym skutočnostiam pribudne sledovanie cirkulujúcich nádorových buniek. Pre ich detekciu sa s veľkou pravdepodobnosťou budú využívať nízkomolekulové fluoreskujúce farbivá. Možno očakávať, že cirkulujúce nádorové bunky budú markerom prognózy i ukazovateľom progresie malignity a liečby. Vedecké bádanie prehĺbi individuálnu terapiu pacientov s nádorovými chorobami. V prehľadovej štúdii sme sa pokúsili analyzovať vedecké poznatky z pozície akceptácie zložitostí a heterogénnosti každého nádoru. Spracovanie obrovského množstva literatúry sme považovali za zmysluplné z hľadiska akceptácie nových poznatkov a teoretickej prípravy na očakávané zmeny diagnostiky a liečby nádorov. Predpokladáme, že prezentované poznatky sú užitočným krokom pre ucelený pohľad do mikroprostredia nádorov.

Kľúčové slová:
angiogenéza – inervácia nádorov – mikroprostredie nádoru – n. vagus – protizápalové pôsobenie nervového systému

Mgr. Zuzana Valášková

www.fmed.uniba.sk

e mail: zuzana.valaskova@fmed.uniba.sk

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