Disrupting the networks of cancer

Abstract

Ecosystems are interactive systems involving communities of species and their abiotic environment. Tumors are ecosystems in which cancer cells act as invasive species interacting with native host cell species in an established microenvironment within the larger host biosphere. At its heart, to study ecology is to study interconnectedness. In ecologic science, an ecologic network is a representation of the biotic interactions in an ecosystem in which species (nodes) are connected by pairwise interactions (links). Ecologic networks and signaling network models have been used to describe and compare the structures of ecosystems. It has been shown that disruption of ecologic networks through the loss of species or disruption of interactions between them can lead to the destruction of the ecosystem. Often, the destruction of a single node or link is not enough to disrupt the entire ecosystem. The more complex the network and its interactions, the more difficult it is to cause the extinction of a species, especially without leveraging other aspects of the ecosystem. Similarly, successful treatment of cancer with a single agent is rarely enough to cure a patient without strategically modifying the support systems conducive to survival of cancer. Cancer cells and the ecologic systems they reside in can be viewed as a series of nested networks. The most effective new paradigms for treatment will be developed through application of scaled network disruption.

Figure 1

Cancer cells act as an invasive species. Many cancers, if left untreated, take on the classic characteristics of an invasive species by spreading to new environments. A classic example of an invasive species is the zebra mussel. Originally only found in the Caspian Sea, it hitched a ride in the ballast tanks of ships and was dumped in the Great Lakes where it has wreaked havoc on the local ecosystem, continuing now to spread all the way to Louisiana. Similarly, cancer cells extravasate from the primary organ, survive circulation by hitching a ride with normal cells, then intravasate and set up residence in a new organ. After a period of lying dormant, these cells eventually grow, destroying the local ecosystem through proliferation and spread (ecologic impact). The migration of prostate cancer cells to bone is a classic example of metastatic spread, causing pain and fracture.

Figure 2

Inhibition of DNA–RNA–protein synthesis. Traditional chemotherapeutic strategies have relied on combining multiple agents that target different levels of the nuclear network. For example, CHOP chemotherapy for lymphoma combines agents that interrupt DNA (C = cyclophosphamide), RNA (H = hydroxydaunorubicin), and protein machineries (O = oncovin or vincristine and P = prednisone) in the nucleus and cytoplasm.

Figure 3

Major signal transduction pathways disrupted in cancer. Targeted therapies in the form of antibodies and small molecules have been designed to inhibit receptors and downstream pathways and/or kinases that have been shown to be disrupted in cancer. Obtained from Wikipedia Commons. Originally derived from the Hallmarks of Cancer (4).