A gyulladásos jelátvitel szerepe a konvencionális vese rák progressziójában

Abstract

“Lymphoreticular infiltrate” e.g. chronic inflammation at the sites of cancer was noticed by Rudolf Virchow in 1863. Today, a range of different scientific findings links cancer and inflammation. It is well demonstrated that several signalling pathways are involved in inflammation operating downstream of oncogenic mutations. Altered gene expression in tumour cells leads to recruitment of inflammatory cells producing chemokines and cytokines present in the stromal microenvironment. These pathways lead to activation of transcription factors (NF-kB, STAT3, HIF-1alpha) in tumour cells resulting in secerning of chemokines and cytokines. This in turn leads to recruitment of various inflammatory cells which also produces, together with the tumour cells, transcription factors. These transcription factors again lead to production of chemokines, cytokines and prostaglandin, continuing the circle of inflammation. This cancer-related inflammation finally leads to change various tumour-associated characteristics, like cell proliferation, survival, angiogenesis, tumour cell migration, invasion, metastasis, inhibition of adaptive immunity and altered response to hormones and chemotherapeutic agents. Tumours are not only mass of cancer cells, but contain many non-malignant stromal cells such as macrophages, lymphocytes, endothelial cells and fibroblasts. All these different cells and the cytokines which they secret, are involved in the neoplastic process, all of which together contributes to growth, progression and dissemination of tumour cells. One group of cells, which are a major component of the lymphoreticular infiltrate, are called tumour-associated macrophages (TAM). TAMs derive from the monocyte-macrophage lineage, and they are brought to the site of inflammation and tumour by chemokines. TAMs produce growth factors, angiogenic factors and protease-enzymes degrading extracellular matrix, all of which favours invasion and metastasis. Tumour-associated neutrophils (TAN) play also a major role in cancer biology. The TANs migrate into tumour tissue under the influence of specific chemokines, cytokines and cell adhesion molecules, specifically the tumour microenvironment is responsible for their recruitment. Several cytokines (e.g CSF2, VEGF, IL-1ß and IL-6) secreted from tumour and stromal cells have been suggested to contribute to neutrophilia and to the induction of suppressive properties to these neutrophils. An inflammatory cytokine network may influence survival, growth, mutation, proliferation, differentiation and movement of tumour cells. Invasion of the tumour largely depends on its ability to degrade its local environment, allowing it to have space to expand. Matrix metalloproteases (MMP) produced by TAMs are activated by inflammatory cytokines, which release the enzymes into the extracellular matrix, digesting the environment, paving the way for invasion. Although several studies have been carried out to analyse the role of inflammatory microenvironment in tumour progression, only few have been concentrated on renal cancer. In the last years by worldwide use of modern imaging techniques the number of incidentally detected pT1, pT2 or pT3 cRCC is steadily growing. In spite of early detection approximately 15-20% of these tumours progress and lead to metastasis. Therefore, it is necessary to find new biomarkers secreted by the tumour cells to estimate the clinical course of cRCC.