Cancer stem cells (CSCs) are tumor-initiating cells (TICs), which are resistant to conventional cancer therapies. As such, CSCs are responsible for driving tumor recurrence, distant metastasis, driving treatment failure, and poor clinical outcomes in cancer patients. Innovative approaches are urgently needed to understand how to control and eradicate CSCs. This may be related to the ability of CSCs to survive and thrive under harsh conditions. Since CSCs are an especially small subset of the tumor cell population, their metabolic and phenotypic properties have remained largely uncharacterized, until recently.
CSCs are strikingly resilient and highly resistant to cellular stress, which allows them to undergo anchorage-independent growth. As a consequence, they form 3D spheroids, which retain the properties of CSCs and stem cell progenitors. In contrast, when subjected to growth in suspension, most “bulk” cancer cells die, via anoikis—a specialized type of apoptosis. As such, the clonal propagation of a single CSC results in the production of a 3D spheroid. Therefore, 3D spheroid formation is a functional read-out for stemness in epithelial cancer cells and allows one to enrich for a population of epithelioid cells with a stem-like phenotype. Interestingly, 3D spheroids are significantly enriched in mitochondrial proteins. These mitochondrial-related proteins include molecules involved in beta-oxidation and ketone metabolism/re-utilization, mitochondrial biogenesis, electron transport, ADP/ATP exchange/transport, CoQ synthesis and ROS production, as well as the suppression of mitophagy. As a consequence, CSCs might become resistant to conventional therapies, by “boosting” ATP production using elevated mitochondrial metabolism.
Consistent with this view, a variety of mitochondrial inhibitors successfully blocked 3D tumor sphere formation, including (i) FDA-approved antibiotics (doxycycline, tigecycline, azithromycin, pyrvinium pamoate, atovaquone, bedaquiline), (ii) natural compounds (actinonin, CAPE, berberine, brutieridin, and melitidin), as well as (iii) experimental compounds [oligomycin and AR- C155858 (an MCT1/2 inhibitor)]. Therefore, new metabolic approaches to targeting CSCs could usher in a whole new era in the field of Medical Oncology, for the prevention of tumor recurrence and treatment failure in cancer patient, leading to long-term extension of post-treatment survival.
This Research Topic will welcome Original Research and Review articles focusing on:
(1) new metabolic approaches to targeting CSCs;
(2) antibiotics for targeting mitochondria in CSCs;
(3) natural compounds for targeting metabolism and mitochondria in CSCs;
(4) new chemical entities for targeting metabolism in CSCs;
(5) drug-repurposing for eradicating CSCs.
Topic Editors MPL and FS hold a minority interest in Lunella Biotech, Inc.
Cancer stem cells (CSCs) are tumor-initiating cells (TICs), which are resistant to conventional cancer therapies. As such, CSCs are responsible for driving tumor recurrence, distant metastasis, driving treatment failure, and poor clinical outcomes in cancer patients. Innovative approaches are urgently needed to understand how to control and eradicate CSCs. This may be related to the ability of CSCs to survive and thrive under harsh conditions. Since CSCs are an especially small subset of the tumor cell population, their metabolic and phenotypic properties have remained largely uncharacterized, until recently.
CSCs are strikingly resilient and highly resistant to cellular stress, which allows them to undergo anchorage-independent growth. As a consequence, they form 3D spheroids, which retain the properties of CSCs and stem cell progenitors. In contrast, when subjected to growth in suspension, most “bulk” cancer cells die, via anoikis—a specialized type of apoptosis. As such, the clonal propagation of a single CSC results in the production of a 3D spheroid. Therefore, 3D spheroid formation is a functional read-out for stemness in epithelial cancer cells and allows one to enrich for a population of epithelioid cells with a stem-like phenotype. Interestingly, 3D spheroids are significantly enriched in mitochondrial proteins. These mitochondrial-related proteins include molecules involved in beta-oxidation and ketone metabolism/re-utilization, mitochondrial biogenesis, electron transport, ADP/ATP exchange/transport, CoQ synthesis and ROS production, as well as the suppression of mitophagy. As a consequence, CSCs might become resistant to conventional therapies, by “boosting” ATP production using elevated mitochondrial metabolism.
Consistent with this view, a variety of mitochondrial inhibitors successfully blocked 3D tumor sphere formation, including (i) FDA-approved antibiotics (doxycycline, tigecycline, azithromycin, pyrvinium pamoate, atovaquone, bedaquiline), (ii) natural compounds (actinonin, CAPE, berberine, brutieridin, and melitidin), as well as (iii) experimental compounds [oligomycin and AR- C155858 (an MCT1/2 inhibitor)]. Therefore, new metabolic approaches to targeting CSCs could usher in a whole new era in the field of Medical Oncology, for the prevention of tumor recurrence and treatment failure in cancer patient, leading to long-term extension of post-treatment survival.
This Research Topic will welcome Original Research and Review articles focusing on:
(1) new metabolic approaches to targeting CSCs;
(2) antibiotics for targeting mitochondria in CSCs;
(3) natural compounds for targeting metabolism and mitochondria in CSCs;
(4) new chemical entities for targeting metabolism in CSCs;
(5) drug-repurposing for eradicating CSCs.
Topic Editors MPL and FS hold a minority interest in Lunella Biotech, Inc.
