The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma

Abstract

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.

Diagnostic Utility of the Immunohistochemical Expression of Serine and Arginine Rich Splicing Factor 1 (SRSF1) in the Differential Diagnosis of Adult Gliomas

“…Autophagic cascade is a catabolic process through which the cells remove their damaged organelles and proteins [ 28 ]. The role of autophagy in cancer still remains controversial, as, in the early stages of tumorigenesis, it seems to play a tumor suppressor role, while in advanced stages, a tumor suppressive function [ 28 ]. The immunohistochemistry represents, at present, the best way to study the autophagy on tissue samples [ 40 ].…”

“…In particular, we tested ATG7 and ATG4 on the whole cohort of GBM and oligodendroglioma cases. ATG7 is located on chromosome 3 and encodes an E1-like activating enzyme that plays a key role for intracellular transport [ 28 ]. ATG4 encodes for a key Cys-protease crucial for the autophagosome-mediated delipidation of ATG8, an essential mechanism of the autophagic cascade.…”

“…and R.C. ), as previously described [ 19 , 28 ]. Briefly, vascular hotspots were identified on tissue sections stained with anti-CD31 immunohistochemical antibody (JC70A; working dilution 1:40; DAKO, Glostrup, Denmark) by a light microscope at 4x and 10x magnifications.…”

“…Sections for authophagy assessment were treated as above-described and the immunohistochemical results were evaluated, as for SRSF1, according to the parameters of IS, ES and IRS, as described above. Both ATG7 and ATG4 exhibited cytoplasmic staining; no nuclear positivity was detected [ 28 ].…”

Development of Radiofluorinated Nicotinamide/Picolinamide Derivatives as Diagnostic Probes for the Detection of Melanoma

“…As mentioned before, 18 F-FPABZA has a similar lipophilicity and relatively low liver uptake when compared with 123 I-BZA, suggesting it could be a potential probe to detect UM and the metastases in the liver. In addition, the genetic background is somewhat different from that of cutaneous melanoma despite a similar morphology between these two types of melanoma being observed [17,19,20]. For example, the expression of P16INK4a, which is related to the pigmentation, is a distinct feature in UM and can be a targeting mechanism for 18 F-FPABZA [17].…”