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ALDH as a tumor marker for pancreatic cancer.

We had the pleasure of reading the article “Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as candidates for tumor markers in patients with pancreatic cancer” published by Jelski et al in the last issue of the Journal of Gastrointestinal and Liver Diseases, in which the Polish research group describe the potential role of ALDH as a tumor marker for pancreatic carcinoma, along with ADH [1]. As methods, they used serum samples from 165 patients diagnosed with pancreatic cancer and 166 healthy controls. ALDH activity (both class I and II isoenzymes) is then measured by fluorometric methods. Even if this is a very interesting study, worthy of further investigations by prospective studies, its final remarks and correlation are somehow incomplete, as further stated in this Letter to the Editor. Some members of the ALDH super-family play key roles in the enzymatic detoxification of both endogenous and exogenous aldehydes and in the formation of important metabolic molecules such as retinoic acid or gammaaminobutyric acid [2]. Thus, mutations in ALDH genes lead to defective metabolism and provide the basic features of diseases such as gamma-hydroxybutyric aciduria, pyridoxine-dependent seizures, Sjögren syndrome or type II hyperprolinaemia [3]. But the most important implication is oncogenesis, as a consequence of impaired retinoic acid synthesis, known to be extremely implicated in stem cell differentiation. Both normal and cancer stem cells share similar characteristics, in that both cell types have the capacity to self-renew and differentiate into multiple cell types [4]. As there is a great need for a universal marker that can identify and isolate these cells, it appears that certain enzymes of the ALDH super-family are able to fulfill this role, being identified in hematopoietic stem cells, melanoma, malignant gliomas and even pancreatic adenocarcinoma, along with other markers such as CD133 [5]. Normal stem cells were shown to contain higher levels of ALDH activity in comparison with their more differentiated progeny, the transit amplifying cells. Confirming this data, Rasheed et al demonstrated that identification of pancreatic cancer stem-like cells is possible through a markerdependent cell selection and the cells that were proven to possess tumor-initiating properties had a high activity of the intracellular enzyme ALDH, apart from the expression of the cell surface markers CD133, CD44 and CD24 [6]. The main flaw in the study published by Jelski et al is the lack of any correlation between the different pathological subtypes of pancreatic cancer and the cancer stem-like cell phenotype. The authors compare their results with other tumor markers used in the clinic, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), but they fail to link the expression of ALDH with the stem-like status, with direct consequence regarding the patients’ clinical prognosis. A high ALDH expression is associated with a worse overall survival in patients that have undergone resection for early stage-disease, according to the report of The Sidney Kimmel Comprehensive Cancer Center in the US. Thus, an enhanced clonogenic growth of ADLH+ cancer cells is certainly linked as having an important role in the long-term outcome of a patient diagnosed with pancreatic adenocarcinoma by mediating or even stimulating cancer dissemination throughout the abdominal cavity and resistance to chemotherapy with 5-fluorouracil (5-FU) or gemcitabine, according to the European Society for Medical Oncology (ESMO) Practice Guidelines [7]. This statement is valid especially after the initial remission of the disease both clinically and according to all diagnostic procedures, because the cytostatic drug will have eliminated most of the more differentiated cancer cells and both the stem-like pool and the malignant tumor niche will have increased in size, resulting in patient death despite the best supportive care.