Title:Cell Hierarchy, Metabolic Flexibility and Systems Approaches to Cancer Treatment
Volume: 14
Issue: 3
Author(s): Patries M. Herst and Michael V. Berridge
Affiliation:
Keywords:
Cancer paradigms, cell hierarchy, drug targeting, metabolic flexibility, stem cells, tissue organization,
Abstract: The proliferative cancer cell paradigm that has driven cancer drug development for the past 50 years has failed
to generate treatments that cure most metastatic adult cancers. This view is supported not only by cumulative experience
with conventional cytotoxic anticancer drugs, but also by the application of highly-targeted anticancer compounds against,
for example, BCR-ABL in CML and mutant BRAF in metastatic melanoma. Such drugs often send their respective cancers
into complete molecular remission but fail to effect cures because a small population of quiescent or slowly selfrenewing
cancer cells that are drug and radiation resistant survive treatment indefinitely. This review explores the grounds
for an emerging cancer paradigm that views cancer as a disorganized tissue with hierarchical cellular compartments in
which the boudaries are less well-defined than in normal tissues with plasticity controlled by epigenetic changes mediated
by the local microenvironment. Increased metabolic flexibility and adaptability give cancer cells an additional survival
advantage that may be able to be targeted with drugs like metformin. Combining approaches that target the increased
metabolic flexibility of cancer cells as well as ablating rapidly-proliferating cells and self-renewing cancer stem cells in
individual cancers are needed to address the holy grail of cancer cure.
