Publikationsdatenbank

Age- and tumor-dependent senescence in canine testis and eye (2019)

Art

Hochschulschrift

Autor

Merz, Sophie (WE 12)

Quelle

Berlin, 2019 — 56 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/24491

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Cellular senescence was discovered in cell culture by Hayflick and Moorhead in 1965 in human fibroblasts. It is primarily characterized by irreversible cell cycle arrest and an altered, enlarged morphology. Senescent cells are thought to accumulate with age in a variety of species including mice, monkey and man. Also, they are thought to drive tumor growth and progression via their senescence-associated secretory phenotype. No known biomarker for cellular senescence is completely specific. Senescence is often triggered by DNA damage, following classical tumor suppressor pathways and activation of cyclin-dependent kinase inhibitors. Looking towards current literature, two potential biomarkers for cellular senescence, DNA-damage marker γH2AX, and cyclin-dependent kinase inhibitor p21, were selected to be tested for transferability on formalin-fixed and paraffin-embedded canine tissue. Most studies on cellular senescence have been conducted in cell culture and to our knowledge none on canine tissues. Human gene products of the DNA damage response are more closely related to dog than to rodent which might make them a superior model. The aim of this study was to test the hypotheses that senescence markers γH2AX and p21 increase with age and in the microenvironment of tumors. Two organ systems that are known to show age-dependent pathologies, testis and eye, were studies for age-dependent increase of senescent cells. For the testis, senescence markers expression was also correlated with age-dependent morphological changes (Leydig cells / intertubular triangle, modified Johnsen score for evaluation of spermatogenesis, interstitial collagen content, epithelial area / tubular area, tubular diameter). Additionally, the microenvironment of testicular (Leydig cell tumor, seminoma, Sertoli cell tumor) and ocular (uveal melanocytoma, ciliary body adenoma) tumors were examined for possible increase of senescent cells. As both used markers are also expressed in tumors, their role as tumor markers in ocular melanocytic tumors (benign uveal melanocytoma, malignant conjunctival melanoma) and testicular tumors was also studied. In the canine testis an age-dependent significant increase could only be noted for p21 in fibroblasts and Leydig cells. However, the expression remained a rare event with only small amounts of cells. Morphological age-dependent changes were only seen in a significant increase of Leydig cells / intertubular triangle and a decrease in spermatogenesis (modified Johnsen score). However, contrary to my expectations, tubular diameters and epithelial areas / tubular areas did not decrease and interstitial collagen content did not increase with age. In the microenvironment of testicular tumors, p21 and γH2AX expression was rare. In testicular tumor cells, γH2AX expression was most prominent in Sertoli cell tumors, followed by seminomas and Leydig cell tumors, whereas p21 expression was most prominent in Leydig cell tumors and low in Sertoli cell tumors and seminomas. These findings correlated with their ki67 indices, where Sertoli cell tumors and seminomas were mitotically more active than Leydig cell tumors. In the canine eye, no age-dependent increase of senescence marker expression could be noted in any examined ocular compartment. In eyes with ocular tumors significantly more p21 and γH2AX expression could be noted in comparison to young eyes particularly in the retina, uvea and lens. However, a tumor-induced pressure increase is likely to have resulted in the higher expression due to cell damage. Tumor cells of benign uveal melanocytomas contained more p21 positive cells than malignant conjunctival melanomas. γH2AX and p21 could not show a convincing age-dependent increase in the canine testis and eye. Morphological changes, the tendency of tumor development and increase in age-related pathologies make it unlikely that the canine testis and eye do not age. Either these tissues do not show an accumulation of senescent cells or a different yet to be found biomarker is needed. A possible bidirectional cross-talk of tumor microenvironment and tumor cells could only be identified for ocular tumors, but this was most likely tumor-induced and not primary age-dependent senescence. P21 as tumor marker for malignancy in melanocytic tumors may be considered.