Fig. 1
The foundational principle underlying aggressive cancers: cancer aggressiveness by-the-numbers. We propose that the absolute number of active (oncogenic) conformations that the cancer harbors are a foundational hallmark of its aggressiveness. The higher the number—the more overspilled the signaling—the higher the heterogeneity. In aggressive cancers the number is extremely high. We dub this hallmark “cancer aggressiveness by-the-numbers”. In this molecular level definition, aggressive tumor candidates are those harboring massive, catalysis-primed oncogenic proteins, produced through overexpression scenarios and strong activating driver mutations. Both generate transcriptional landscapes signaling by-the-numbers scenario.14,25 Overexpression of oncogenic proteins is caused by an increase in gene expression due to epigenetic and genetic mechanisms, involving super-enhancers, hybrid gene fusions resulting from the combination of two independent genes, copy number alterations with lost or gained DNA segments, and an increase in signaling to target genes. A high propensity of active conformations shifts the population from an inactive state (gray spheres) to a constitutively active conformation (red RTKs and spheres).412 This leads to an increase in the number of active molecules (blue RTKs and spheres) of the corresponding protein node, resulting in an elevation in active transcription factors (small blue spheres with arrows), which in turn leads to the overexpression of oncogenes. Our molecular level definition updates the traditional definition of the National Cancer Institute, which defines an aggressive cancer as one that “forms, grows, or spreads rapidly and requires more intensive or severe treatment than usual”. For clarity, see the section on questions and clinical implications. It defines an active protein conformation, how their number can be assessed, explains why thresholds are still unavailable and challenging to establish. It also addresses how to measure expression of super-enhancers and overexpression, and more. Tumor suppressors are not included
