Hallmarks of cancer-the new testament

Abstract

Diagnosis and treatment of disease demand a sound understanding of the underlying mechanisms, determining any Achilles' heel that can be targeted in effective therapies. Throughout history, this endeavour to decipher the origin and mechanism of transformation of a normal cell into cancer has led to various theories-from cancer as a curse to an understanding at the level of single-cell heterogeneity, meaning even among a single sub-type of cancer there are myriad molecular challenges to overcome. With increasing insight into cancer genetics and biology, the disease has become ever more complex to understand. The complexity of cancer as a disease was distilled into key traits by Hanahan and Weinberg in their seminal 'Hallmarks of Cancer' reviews. This lucid conceptualization of complex cancer biology is widely accepted and has helped advance cancer therapeutics by targeting the various hallmarks but, with the advancement in technologies, there is greater granularity in how we view cancer as a disease, and the additional understanding over the past decade requires us to revisit the hallmarks of cancer. Based on extensive study of the cancer research literature, we propose four novel hallmarks of cancer, namely, the ability of cells to regress from a specific specialized functional state, epigenetic changes that can affect gene expression, the role of microorganisms and neuronal signalling, to be included in the hallmark conceptualization along with evidence of various means to exploit them therapeutically.

Keywords: cancer hallmarks; de-differentiation; epigenetics; microbiome; neuronal signalling.

Figure 1.

Hallmark flower.

Figure 2.

Novel hallmarks of cancer.

Figure 3.

Tumour defiance of Waddington landscape. (a) Waddington landscape depicting the unidirectional nature of differentiation, adapted based on the concept of [8]. (b) The forgotten hallmark Dedifferentiation: Dedifferentiation from terminally differentiated neuron, astrocyte and oligodendrocyte, as well as transdifferentiation of neuron and astrocyte to endothelial cells.

Figure 4.

Transdifferentiation approach to therapy. Following combination of PPARγ agonist rosiglitazone (an anti-diabetic drug) + MEK inhibitor—cancer cells are converted to functional adipocytes, adapted based on [38].

Figure 5.

The road better not taken: intertwined nature of epigenetic instability and genetic instability in riding over the road of hallmarks towards tumourigenesis.

Figure 6.

Epigenetic crossroads: multitude of studies supporting the epigenetic progenitor model.

Figure 7.

Coexistence.

Figure 8.

(a,b) Microbiome tug-of-war hypothesis for CRC latency: improvization of the Vogelgram [117], with an explanation of the role of bacteria in multi-step CRC progression.

Figure 9.

Tumour promoting inflammation triggered by mycobiome. (a) Sphincter of Oddi. (b) The mannose-binding lectin (MBL) pathway of complement activation, adapted based on [134].

Figure 10.

Blood vessels and nerves in tandem.

Figure 11.

Chronic stress-dependent sympathetic nerve signalling triggering tumour growth via a feedforward loop.

Figure 12.

Synaptic interaction between presynaptic neuron and glioma via AMPA receptor.

Figure 13.

Parasitic tripartite synapse: B2BM colonization of brain using glutamate from the fake tripartite synapse, adapted based on [184].