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Aldehyde dehydrogenases (ALDHs) as emerging biomarkers of cancer stem cells and therapeutic implicatios (Master thesis)

Μπαλάσκα, Κωνσταντίνα/ Balaska, Konstantina

Cancer stem cell hypothesis has drawn much attention the past few years even though it was proposed several decades ago, primarily because it is a theory that can provide explanations concerning many parameters of the multifaceted disease of cancer. Up to a certain extent, it is proven that cancer stem cells exist and are the origin not only for the initiation and progression of carcinomas, but mainly for metastasis and recurrence that are often observed in cancer patients and comprise the underlying cause for the high death rates recorded worldwide. Thus, it has become apparent that to address this issue, it is pivotal initially to identify these cells within the tumor mass and then attempt to target them with specific compounds via properly constructed carriers, in order to eliminate them. Aldehyde dehydrogenases (ALDHs) are a family of enzymes that are implicated in many metabolic procedures, especially in the oxidation of toxic aldehydes while they also possess antioxidant, regulatory and structural functions. In the human genome, 19 functional ALDH genes have been discovered so far, each one having a fundamental role in cellular homeostasis and metabolism, a fact that is highlighted by a variety of pathologic conditions and clinical syndromes that emerge upon loss of their function. For many decades speculations existed concerning the potential role of ALDHs in cancer progression, but not until recently, there existed the proper methodology for their detection and measurement in vivo. The Aldefluor assay, therefore, comprises nowadays, an indispensable tool in cancer stem cell research since a plethora of studies have intertwined elevated ALDH expression with cancer stem cell phenotype. This review explored the potential use of ALDHs as biomarkers of cancer stem cells in breast, ovarian, lung and prostate cancers, based on recent literature. After thorough analysis, it is concluded that although there exist studies that failed to acknowledge ALDHs as specific cancer stem cell markers for the certain cancer types investigated, the vast majority of the scientific community endorses the use of ALDHs as biomarkers of cancer stem cells. More specifically, a plethora of studies correlated high ALDH activity with ALDH1 isoform, however, other ALDH isoforms, such as ALDH1A3, ALDH7A1, ALDH3A1 have been lately detected at high levels in several carcinomas and are speculated to be involved in carcinogenesis as well. Additionally, ALDH expression was often linked with aggressive behavior, including increased tumorigenicity, sphere-forming capacity, invasiveness, metastatic potential and chemotherapy/radiotherapy resistance. ALDH+ cancer cells were reported to displayed a distinct gene expression profile, which corresponded with fundamental properties attributed to cancer stem cells, such as elevated levels of genes implicated in self-renewal, as well as genes characteristic of high proliferative and metastatic capacity. Consequently, ALDH activity could be exploited as a prognostic/predictive biomarker, at least for some cancer types, especially in correlation with other known cancer stem cell surface markers. ALDH expression, thus, could facilitate the detection of cancer stem cells since it is widely accepted that therapeutic efficacy could be enhanced if treatment regimens incorporate compounds that eliminate both the bulk of the tumor as well as the resistant cancer stem cell compartment. Moreover, selective ALDH inhibition could provide additional assistance in combination with the classic anticancer agents, so as to override chemotherapy resistance and prevent relapse.