Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review

Abstract

Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, cancer cells acquire and exhibit several characteristics including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, and expressing an immune phenotype, which allow them to evade recognition and destruction through cognate immune cells. In addition, cancer cells may acquire the ability to reprogram their metabolism in order to further promote growth, survival, and energy production. This phenomenon, termed metabolic reprogramming, is typical of all solid tumors, including squamous carcinomas of the head and neck (SCCHN). In this review, we analyze the genetic and biological mechanisms underlying metabolic reprogramming of SCCHN, focusing on potential therapeutic strategies that are able to counteract it.

Keywords: Akt; TP53; Warburg effect; head and neck squamous cell carcinoma; immunosurveillance; metabolic reprogramming.

Figure 1

Distinctive features between metabolism in normal and cancer cells. The greater thickness of the arrows indicates the greater frequency of metabolic pathway occurring. PPP: pentose phosphate pathway; OxoPhos: oxidative phosphorylation; FA: fatty acids.

Figure 2

Intracellular down-stream pathways stimulated by PI3K-Akt-mTOR activation. The direct consequences are an (1) increase in glucose uptake through GLUT4 upregulation; (2) increase in protein synthesis through S6 (ribosomal subunits) up-regulation; (3) increase in glycogen synthesis (which is available thus for the glycolysis); (4) increase in fatty acids synthesis through ATP Citrate lyase up-regulation and ultimately (5) block of FOXO which acts as tumor suppressor genes, increasing cell proliferation. PI3K: Phosphatidyl Inositol 3 Kinase; pip2: Phosphatidyl Inositol 2-phosphate; pip3: Phosphatidyl Inositole3 phosphate; PDK1: phosphoinositide dependent kinase-1, mTORCH: mammalian target of rapamycin complex; AS160: Akt substrate of 160 kDa; TSC 1/2; hamartin–tuberin complex; foxo: Fork head box O3; GSK3: Glycogen synthase kinase 3; GS: Glycogen synthase; Rheb: Ras homologue enriched in brain.

Figure 3

During cancer progression, cancer cells acquire various skills, in particular the ability to alter the cell cycle/survival, the ability to evade the immune response, and the ability to reprogram their own metabolism. An ideal clinical approach could use drugs capable of acting on one or more of the aforementioned skills.