Metabolic Modification in Gastrointestinal Cancer Stem Cells: Characteristics and Therapeutic Approaches

Abstract

Currently, there is much interest in the characterization of metabolic profiling of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal capacity. Indeed, ever-growing evidence indicate that metabolism and stemness are highly intertwined processes in tumor tissue. In this review, we analyze the potential metabolic targeting strategies for eradicating CSCs that could help to develop a more effective therapeutic approach for gastrointestinal cancers. Indeed, the successful elimination of a tumor requires an anticancer therapy that affects both cancer cells and CSCs. The observation that gastrointestinal CSCs possess higher inducible nitric oxide sinthase (iNOS) expression, lower reactive oxygen species (ROS) production, and a different metabolism respect to no-CSCs tumor cells has paved the way to develop drugs targeting CSC specific signaling. In particular, several studies have highlighted that metformin, aldehyde dehydrogenase 1, and iNOS inhibitors selectively suppressed CSC growth and that combinatorial therapy of them with standard chemotherapeutic drugs had a synergistic effect resulting in reduced tumor burden and delayed tumor recurrence. Thus, the possibility of combining specific CSC metabolism inhibitors with existing therapeutic approaches could have profound anticancer effects, changing the conventional treatment approaches to gastrointestinal cancers. J. Cell. Physiol. 231: 2081-2087, 2016. © 2016 Wiley Periodicals, Inc.

Cancer Metabolism: Fueling More than Just Growth

“…However, highly proliferating normal cells, such as intestinal cells or cells during embryonic development, feature similar proliferative metabolism, such as pyruvate kinase M2 isoform (PKM2) expression or high folate demand (Barker, 2014; Di Francesco et al, 2016; Kim et al, 2015b). Such cells are impacted by these chemotherapeutic strategies, and this becomes the basis for side effects, dose limiting toxicities, and chemotherapy contraindication in pregnancy.…”

Aptamer-Based Therapeutic Approaches to Target Cancer Stem Cells

“…Interestingly, the last step of tumour evolution is always accompanied by a reduction of CSC expansion when the patient is in remission or ultimately succumbs to the tumour. This suggests that uncontrolled CSC expansion eventually leads to their destruction and is referred to as “CSC overshot”, a phenomenon similar to what occurs in ecosystems when the number of a species exceeds the maximum bearing capacity of their surroundings 24 ( Fig. 2 B ).…”

“…2 B ). It is now understood that the number of CSCs within the same tumour dynamically changes during the entire malignant process, developing along a steep hierarchy in the primary stage consisting of a small number of heterogeneous CSCs and a larger number of differentiated non-CSCs, towards a hierarchy containing continually increasing proportions of CSCs, and constant progress to a very shallow hierarchy in the metastatic stage where the proportion of CSCs reach a plateau 23 , 24 ( Fig. 2 B ).…”

“…These obstacles may include leaky blood/lymphatic vessels, extracellular matrix (ECM) in which therapeutic agents may accumulate and tumour cell membranes that the agents have to penetrate through before reaching the peri-nuclear regions of CSCs 30 . These barriers may lead to impaired drug uptake, excessive drug degradation and short drug circulation within the tumour 24 , 31 . In addition, agents without cancer targeting moieties may indiscriminately diffuse into both normal and tumour blood vessels leading to unwanted side effects 31 .…”

Nanomedicine strategies for sustained, controlled, and targeted treatment of cancer stem cells of the digestive system

“…For example, gastrointestinal CSCs showed higher inducible nitric oxide synthase (iNOS) expression, lower reactive oxygen species (ROS) production, and a different metabolic profile with respect to non-CSCs. Aerobic glycolysis blockade, oxidative stress-based therapies, and nitric oxide synthase inhibition target the gastrointestinal CSCs and could have profound anticancer effects[ 69 ].…”