Autophagy patterns and prognosis in uveal melanomas

Abstract

Autophagy is a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. It has been claimed that, under certain conditions, such a process may be associated with tumor progression. In this study, the autophagic activity was investigated in a series of 99 uveal melanomas after immunohistochemical staining for the autophagy-associated proteins MAP1LC3A and BECN1, most commonly known as LC3A and Beclin 1, respectively. These were assessed in parallel with the hypoxia-inducible factor 1a (HIF1A) and its downstream protein lactate dehydrogenase 5 (composed by five LDHA subunits). Increased autophagic reactivity, detected by MAP1LC3A or BECN1, was associated with intense pigmentation and tumor hypoxia. Uveal melanomas with extensive overexpression of BECN1 or those with underexpression of this protein were associated with the worst prognosis, but the former manifested metastases much earlier than the latter; only 58% of patients with extensive BECN1 overexpression were alive at 4 years, compared with 80% of patients with underexpressed patterns. It is concluded that autophagy is commonly upregulated in uveal melanomas, and may be associated with hypoxia and intense pigmentation. There is a strong association between extensive BECN1 overexpression and early metastases/poor prognosis, and between underexpression of this protein and late metastases/better prognosis.

Autophagy and Bcl‐2/BNIP3 death regulatory pathway in non‐small cell lung carcinomas

“…As previously reported (39), no association between Beclin 1 expression and patients' survival was noted. This notion however is in contrast with our earlier findings in colorectal carcinomas (41) and in uveal (42) and cutaneous (43) melanomas, where Beclin 1 expression showed a biphasic correlation with prognosis, as well as with the worse prognosis of the highly Beclin 1-positive endometrioid carcinomas (44). Then again, Beclin 1 expression showed no association with LC3A reactivity patterns in lung carcinomas, and this probably accounts for the aforementioned observation, as LC3A paranuclear expression and LC3A-positive SLS were associated with poor prognosis in lung carcinomas (4).…”

Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients

“…Upon induction of autophagy, LC3-I is subsequently conjugated with phosphatidylethanolamine to become LC3-II. Thus, the accumulated puncta and levels of cleaved LC3/LC3-I could correlate with autophagic activity, which has been used in several carcinomas, including breast carcinomas, malignant melanomas, pancreatic cancers, colorectal adenocarcinomas, non-small cell lung carcinomas, and uveal melanomas [9,27,[32][33][34][35][36]. Since p62 (SQSTM1) can be efficiently degraded by autophagy through direct binding to Atg8/LC3 on the autophagosome membrane, the expression of p62 inversely correlates with autophagic activity [33,37,38].…”

Autophagy and cancer – issues we need to digest

“…A recent study has shown that the induction of autophagy following ECM detachment is a prosurvival mechanism that prevents cells from undergoing anoikis (Fung et al, 2008). There is clinical evidence that hyperactive autophagy in melanoma and hepatocellular carcinoma leads to early metastasis and poor prognosis (Ding et al, 2008;Giatromanolaki et al, 2011).…”

“…As a result, accumulation of autophagosomes in tumour cells has been shown to correlate with clinical outcomes in cancer patients and this has raised the possibility of using autophagy markers as a prognostic tool in cancer treatment (Morselli et al, 2011;Giatromanolaki et al, 2011). For example, melanomas with higher levels of autophagosomes are less likely to respond to temozolomide and sorafenib treatment, which leads to a poorer clinical outcome in patients (Giatromanolaki et al, 2011). However, caution should be taken, because correlative studies of this kind rely on either the absence or presence of accumulated autophagosomes as a readout of autophagy.…”