Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas.
OBJECTIVE
The microtubule-associated protein 1 light chain 3 (LC3A) is an essential component of the autophagic vacuoles, forming a reliable marker of autophagic activity. In a previous study, the authors showed that LC3A immunohistochemistry renders three patterns of autophagic expression in breast carcinomas: diffuse cytoplasmic, perinuclear and 'stone-like' intracellular structures (SLS), each with a distinct prognostic relevance.


METHODS
Tumour tissues from 155 patients with stage IIA-III colorectal adenocarcinomas, treated with surgery alone, were assessed immunohistochemically for LC3A. Median values were used as cut-off points to separate groups into low and high autophagic activity. Associations with prognosis and with lactate dehydrogenase-5 (LDH5) were sought.


RESULTS
High SLS counts were associated with metastases and poor prognosis, while the prominence of the perinuclear pattern was linked to localised disease and good prognosis. The cytoplasmic pattern was irrelevant. Furthermore, patients with increased SLS numbers, but suppressed perinuclear expression, were associated with LDH5 overexpression and had an extremely poor prognosis (3-year survival 16.5%). The prognosis improved considerably when high SLS counts were accompanied by intense perinuclear expression (3-year survival 67%) and were optimal when SLS numbers dropped below median values, irrespective of perinuclear status (3-year survival 94-100%). Multivariate analysis showed that SLS and perinuclear patterns were independent predictors of death events.


CONCLUSIONS
Perinuclear LC3A accumulation in colorectal tumour cells is a marker of good prognosis, presumably reflecting a basal autophagic activity. An abnormal or excessive autophagic response, as indicated by increased numbers of SLS, is linked to metastasis and poor prognosis.
Giatromanolaki
Alexandra
A
Department of Pathology, Democritus University of Thrace and University General Hospital of Alexandroupolis, Alexandroupolis, Greece.
Koukourakis
Michael I
MI
Harris
Adrian L
AL
Polychronidis
Alexandros
A
Gatter
Kevin C
KC
Sivridis
Efthimios
E
D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis
D014408:Biomarkers, Tumor; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins