Red, theory; black, fact
Keywords:
Small-world, network, neuromodulator, hub node, cancer state, behavioral state, robustness, network overlap
The refractoriness of cancer (its treatment resistance) is thought by a few authors I read forty years ago to be due to a kind of in-body evolutionary process made possible by the high mutation rate characteristic of these cells. The anticancer drugs we apply to kill the cancer exert an evolutionary selection pressure on the individualistic cancer cells, killing most of them but leaving a residue of accidentally resistant cells that happen to have mutations conferring resistance. These resistant cells then grow back the cancer in a relapse, even harder to kill than before. And so it goes through treatment after treatment until the patient is dead.
But what if that’s wrong?
An alternative explanation of cancer refractoriness seems possible, in terms of a “cancer state” that is sustained by re-entrant (circulating) metabolic signalling pathways that form a small-world network (SWN). Curing the cancer requires extinguishing the reentrant activity, but this is difficult because of the robustness of the SWN. If one node in the network is pharmacologically ablated, the signalling can always flow around it by alternative pathways through the network. Thus, robustness becomes refractoriness.
The robustness of SWNs depends on their hub nodes—nodes with an unusually large number of connections. The state theory of cancer articulated here therefore directs us to pharmacologically target the hub nodes for greatest therapeutic efficacy. However, a practical therapy also requires selectivity. If we make the leap to assuming that all cellular actions involve entering and leaving states, that all states are identifiable with particular re-entrant SWNs, and that due to the parsimony of evolution, there is much overlap among SWNs and sharing of nodes, it seems possible that the set of hub nodes of a particular SWN can be used as a biochemical address for that SWN, leading to the desired selectivity. The other overlapping SWNs in the treated cell can survive the loss of only one or two hub nodes due to treatment, but not the targeted SWN, which loses all of them.
However, these ideas predict zero response to a single drug, not a large but temporary response. Progress in resolving this will involve consideration of state-trait relationships. For example, a predilection for entering a particular state could be a genetically determined trait, and some states could exist that suppress DNA repair, leading to increasing genetic diversity. Lack of selectivity of anticancer drugs could also be a factor, so that the same drug could delete multiple hub nodes but not all of them.
Behavioral states such as aggression and siege mentality (the foibles of, respectively, capitalism and communism) also show refractoriness that may have the same cause. In these cases, some likely hub nodes are the neuromodulatory cell groups of the brainstem. An example is the locus ceruleus (LC), which distributes noradrenaline widely in the brain. (Noradrenaline is also the postganglionic transmitter of most of the sympathetic nervous system.) The existence of disciplines such as meditation suggests that some of the SWNs incorporating the LC also incorporate hub nodes in cerebral regions accessible to consciousness, probably including the brain’s language areas. More visceral hub nodes such as blood sugar level are probably also included.
The need to treat multiple hub nodes simultaneously to extinguish maladaptive reentrant signalling may have been stated before, but in proto-scientific terms:
“Put on the whole armour of God…”
Saint Paul
The caddy is stocked with oil, vinegar, a mixing bottle, pepper, and cinnamon.
