Perspective on the dynamics of cancer

Abstract

Background: The genetic diversity of cancer and the dynamic interactions between heterogeneous tumor cells, the stroma and immune cells present daunting challenges to the development of effective cancer therapies. Although cancer biology is more understood than ever, this has not translated into therapies that overcome drug resistance, cancer recurrence and metastasis. The future development of effective therapies will require more understanding of the dynamics of homeostatic dysregulation that drives cancer growth and progression.

Results: Cancer dynamics are explored using a model involving genes mediating the regulatory interactions between the signaling and metabolic pathways. The exploration is informed by a proposed genetic dysregulation measure of cellular processes. The analysis of the interaction dynamics between cancer cells, cancer associated fibroblasts, and tumor associate macrophages suggests that the mutual dependence of these cells promotes cancer growth and proliferation. In particular, MTOR and AMPK are hypothesized to be concurrently activated in cancer cells by amino acids recycled from the stroma. This leads to a proliferative growth supported by an upregulated glycolysis and a tricarboxylic acid cycle driven by glutamine sourced from the stroma. In other words, while genetic aberrations ignite carcinogenesis and lead to the dysregulation of key cellular processes, it is postulated that the dysregulation of metabolism locks cancer cells in a state of mutual dependence with the tumor microenvironment and deepens the tumor's inflammation and immunosuppressive state which perpetuates as a result the growth and proliferation dynamics of cancer.

Conclusions: Cancer therapies should aim for a progressive disruption of the dynamics of interactions between cancer cells and the tumor microenvironment by targeting metabolic dysregulation and inflammation to partially restore tissue homeostasis and turn on the immune cancer kill switch. One potentially effective cancer therapeutic strategy is to induce the reduction of lactate and steer the tumor microenvironment to a state of reduced inflammation so as to enable an effective intervention of the immune system. The translation of this therapeutic approach into treatment regimens would however require more understanding of the adaptive complexity of cancer resulting from the interactions of cancer cells with the tumor microenvironment and the immune system.

Keywords: Cancer associated fibroblasts; Cancer dynamics; Cancer inflammation; Cardinal signaling pathways; Dysregulated cellular processes; Tumor associated macrophages; Tumor immunosuppression; Tumor microenvironment.

Fig. 1

Integrated signaling and metabolic cellular processes. Cellular metabolism is regulated by key signaling pathways of growth and proliferation which include RAS-ERK and PI3K-MTOR. These pathways are also involved in the regulation of the cell cycle, autophagy, survival and apoptosis in concert with the TGFβ, NF-χβ, and P53 signaling pathways among others

Fig. 2

TME Cells’ interactions. The synergetic interactions between CAFs, TAMs and cancer cells promote inflammation, immunosuppression and tumor growth. The dotted lines show indirect interactions, as is the case with the release of TGF-β from the extracellular matrix (ECM) degraded by the actions of proteases secreted by cancer cells

Fig. 3

Dysregulation probabilities of cellular pathways. The dysregulation probabilities clearly distinguish the different cancer types and points to a significant differential in the likelihood of altered regulation across different cellular processes. The probabilities are computed using the set of 127 genes and relevant data reported in [27] (Additional file 1: Table S1)

Fig. 4

Cardinal pathways mediating the TME-CCs interactions. The TME-CCs interaction dynamics are postulated to be driven by cancer cells enlisting of CAFs and TAMs and the subsequent induction of an inflammation and growth promoting tumor microenvironment

Fig. 5

Dysregulation probabilities for glycolysis, the TCA cycle, genome integrity, survival and the cell cycle progression through the restriction point

Fig. 6

Cancer as a stochastic system. Cancer is postulated to be initiated by the genetic-driven dysregulation of metabolism which is permitted to drive growth and proliferation due to the abrogation of the cell cycle restriction checkpoint and the inflammatory, survival and nutritional feedback of the TME. Therapeutic disruptions of the effectors of cancer growth dynamics are noted and qualified as potentially effective or ineffective based on the level and bandwidth of sensitivity to genomic instability