Somatic evolution of head and neck cancer - biological robustness and latent vulnerability

Abstract

Despite recent advancements in multidisciplinary treatments, the overall survival and quality of life of patients with advanced head and neck squamous cell carcinoma (HNSCC) have not improved significantly over the past decade. Molecular targeted therapies, which have been addressed and advanced by the concept of "oncogene addiction", have demonstrated only limited successes so far. To explore a novel clue for clinically effective targeted therapies, we analyzed the molecular circuitry of HNSCC through the lens that HNSCC is an evolving system. In the trajectory of this somatic evolution, HNSCC acquires biological robustness under a variety of selective pressures including genetic, epigenetic, micro-environmental and metabolic stressors, which well explains the major mechanism of "escaping from oncogene addiction". On the other hand, this systemic view appears to instruct us approaches to target latent vulnerability of HNSCC that is masked behind the plasticity and evolvability of this complex adaptive system.

Figure 1

Tumor evolutionary trajectory and twelve hallmarks of HNSCC. HNSCC evolves form normal epithelium to advanced tumors. In this process, intracellular molecular circuitry or gene regulatory network achieves transient equilibrium state, “cancer attractor”, which is depicted as a basin in the trajectory. A variety of genetic, epigenetic, micro‐environmental and metabolic stressors work as selective pressures. To acquire advanced fitness, immature clone goes up to the higher attractor state. In accordance with evolution, the state of each attractor becomes more robust, although, in parallel, the hurdle to the next attractor becomes higher. When compared to the normal cell differentiation trajectory for which visual representation of attractor was originally developed, cancer evolutionary trajectory seems to be the reveres movement, i.e., de‐differentiation. In our opinion (see Figure 2), cancer stem cell (CSC) of HNSCC (purple) lies in the highest attractor. Of note, for simplification we depicted the trajectory of HNSCC in a two‐dimensional format, but it should be multi‐dimensional and the trajectory is not a single route. We postulate that in this evolutionary trajectory HNSCC acquires twelve hallmarks. As discussed in Figure 2 and text, we categorized the epithelial–mesenchymal transition (EMT) and CSC as the distinctive properties that the most advanced HNSCC display.

Figure 2

Proposed mechanism of the development of cancer stem cell (CSC) (purple) in HNSCC and its relation to sensitivity to DNA‐damaging agents, and tumor recurrence and metastasis. CSCs of HNSCC appear to originate from cancer cells that have undergone processes of multistage carcinogenesis (orange and green) at the advanced stage of tumor progression, since a majority of early stage tumors are cured by chemoradiation or irradiation alone (i.e., chemoradioselection) lacking the CSC phenotype. Thus, the origin of HNSCC is not likely CSC. However, this model does not exclude the possibility that CSCs of HNSCC originate from normal stem cells (white) that accumulated a series of abnormalities. CSCs can survive treatments with DNA‐damaging agents and propagate recurrent tumor. CSCs that have undergone epithelialߝ;mesenchymal transition (EMT) can migrate as “migrating CSCs” (jagged purple) and propagate metastatic tumors after they have, in turn, undergone mesenchymal epithelial transition (MET). Recurrent and metastatic tumors appear to be composed of relatively homogeneous cell population that that has two distinctive properties: insensitive to DNA‐damaging therapy and ability to rapidly expand gross tumor volume. For more details see text.