Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

Abstract

The present study was carried out in order to examine molecular alterations of extracellular matrix (ECM), associated with cell-cell communication in conventional (clear-cell) renal cell carcinomas (cRCCs) influenced by persistent long-term, low-dose ionizing radiation (IR) exposure to patients living more than 19 years after the Chernobyl accident in Cesium 137 (137Cs)-contaminated areas of Ukraine. The ECM major components such as fibronectin, laminin, E-cadherin/beta-catenin complexes and p53 tumor suppressor gene protein, and transforming growth factor beta 1 (TGF-beta1) were immunohistochemically (IHC) evaluated in cRCCs from 59 Ukrainian patients, which represented 18 patients living in non-contaminated areas and 41 patients from 137Cs-contaminated areas. In contrast, a control group of 19 Spanish patients with analogue tumors were also investigated. For IHC evaluation, a tissue microarray technique was used. Decrease or loss and abnormal distribution of fibronectin, laminin, E-cadherin/beta-catenin complexes accompanied by elevated levels of p53 and TGF-beta1 were detected in the Ukrainian cRCCs from 137Cs-contaminated areas with statistically significant differences. Thus, our study suggests that chronic long-term, low-dose IR exposure might result in global remodeling of ECM components of the cRCCs with disruption in peri-epithelial stroma and epithelial basement membranes.

Chernobyl-Related Cancer and Precancerous Lesions: Incidence Increase Vs. Late Diagnostics

“…The increase in "aggressiveness" of the RCC was probably caused by detection in Ukraine of previously neglected cancers by means of improved diagnostic methods. In accordance with this hypothesis, the tumors from Ukraine had on average a higher histological grade than the control cases from Spain (Romanenko 2006a;Jargin 2007). In particular, "the dramatic increase of aggressivity and proliferative activity" was found in RCC from Ukraine (Romanenko et al 2000a), while "the majority of the high grade tumors occurred in the Ukrainian (rather than in the Spanish) groups" (Romanenko et al 2001a), which can be explained by the on average earlier detection of malignancies in Spain.…”

Ionizing Radiation Predisposes Nonmalignant Human Mammary Epithelial Cells to Undergo Transforming Growth Factor β–Induced Epithelial to Mesenchymal Transition

“…If moderate radiation doses can prime preneoplastic cells to undergo EMT, it could accelerate cancer progression. Interestingly, a recent study shows that conventional renal cell carcinomas of the Ukrainian patients living in the radiationcontaminated areas exhibited significantly higher levels of TGFh expression compared with similar tumors in populations in uncontaminated areas (49). These tumors were characterized by decreased or abnormal distribution of fibronectin, laminin, and E-cadherin/h-catenin, suggesting that chronic low-level radiation exposure in humans might indeed shift tumors toward a mesenchymal phenotype.…”

Gene Expression Response of Mice after a Single Dose of 137Cs as an Internal Emitter

“…Integrin signaling connects the ECM with the actin cytoskeleton to control some of these functions (49), and we found many GO categories related to actin and cytoskeletal functions overrepresented with the same pattern of early upregulation and later down-regulation, suggesting a major impact of this system in regulating both early and late responses. Interestingly, a study of clear-cell renal cell carcinomas from patients living in 137 Cs contaminated areas near Chernobyl found decreased expression and altered distribution of ECM proteins compared to tumors from unexposed controls (50), suggesting that chronic exposure to 137 Cs could result in broad remodeling of the ECM. The reported decreases in protein expression are consistent with the decreased gene expression at days 20 and 30 after 137 Cs exposure in our study.…”