The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression

Abstract

Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells (CSCs), a cancer cell sub-population possessing a panel of stem-like properties, such as a self-renewal ability and multipotency potential. CSCs are associated with enhanced chemoresistance due to the enhanced efflux of chemotherapeutic agents and the existence of powerful antioxidant and DNA damage repair mechanisms. The distinctive characteristics of CSCs make them ideal targets for clinical therapeutic approaches, and the identification of efficient and specific CSCs biomarkers is of utmost importance. Aldehyde dehydrogenases (ALDHs) comprise a wide superfamily of metabolic enzymes that, over the last years, have gained increasing attention due to their association with stem-related features in a wide panel of hematopoietic malignancies and solid cancers. Aldehyde dehydrogenase 1B1 (ALDH1B1) is an isoform that has been characterized as a marker of colon cancer progression, while various studies suggest its importance in additional malignancies. Here, we review the basic concepts related to CSCs and discuss the potential role of ALDH1B1 in cancer development and its contribution to the CSC phenotype.

Keywords: ALDHs; CSCs; aldehyde dehydrogenase 1B1; aldehyde dehydrogenases; cancer; cancer stem cells.

Figure 1

The process of malignant transformation. Cancer is a multi-staged procedure in which cells gradually acquire malignant characteristics. Initiation includes certain genetic/epigenetic changes resulting in the deregulated control of processes, such as cell-cycle progression, apoptosis, and proliferation. The clonal expansion of the initiated cell, which exhibits defective apoptosis, abnormal cell-cycle arrest, and excessive proliferation, leads to the formation of a preneoplastic lesion of closely attached cells. During progression, the genetically unstable preneoplastic cells progressively accumulate novel, malignant-related properties, such as the ability to escape from immune surveillance, migrate and invade new tissues, and form new tumors.

Figure 2

The clonal or stochastic cancer development model. In the clonal model, every cancer cell has the potential to promote the development of a new tumor. The driving force of tumor heterogeneity is the genetic instability of cancer cells that results in the accumulation of DNA alterations and, consequently, the formation of cancer cells with different genotypes and, thus, phenotypes.

Figure 3

The hierarchical or cancer stem cell development model. In the hierarchical model, cancer stem cells are able to self-renew and differentiate into multiple, different cancer cell types and, thus, induce the formation of a new tumor with the same heterogeneity as the initial one. Some studies support the existence of distinct CSC subpopulations within a tumor. An important aspect that has not yet been clarified is whether CSCs originate from normal stem cells undergoing malignant transformation or whether they derive from differentiated cells that acquire stem-related properties during carcinogenesis. Finally, certain reports demonstrate the plasticity of CSCs, which appear to have the potential to switch between the CSC and the non-CSC states through unknown mechanisms.

Figure 4

Methods for isolating CSC-like cells. A variety of different methods have been developed for isolating and enriching CSCs from different samples. Often these methods are combined to achieve efficient isolation of CSCs. (A) Selection based on the expression of certain cell-surface markers. (B) Isolation based on the ability of cells to efflux certain stains. (C) Enrichment based on the formation of 3D tumorspheres. (D) Isolation through determining ALDH enzymatic activity.

Figure 5

Techniques for evaluating the CSC-related properties of cancer cells. Several methods can be applied to characterize the CSC phenotype of a certain sample of cancer cells. A holistic approach should apply more than one method. (A) Assessing the ability of cancer cells to induce heterogeneous tumors in xenograft models. (B) Monitoring the endurance against chemotherapeutic agents and/or radiation. (C) Examining the regulation of CSC markers. (D) Evaluating their multipotency.

Figure 6

Aldehyde dehydrogenases catalyze the oxidation of an aldehyde to its corresponding carboxylic acid.

Figure 7

Enzymatic activities of aldehyde dehydrogenase 1B1 (ALDH1B1) (Chemical structures are from PubChem (https://pubchem.ncbi.nlm.nih.gov/) accessed on 5 December 2022) [184,185,186,187,188,189,190,191].

Figure 8

ALDH1B1-associated non-cancer pathologies [195,196,197,198,199,200,201].