The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.

The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.

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Targeting the phosphoinositide 3-kinase pathway in cancer.

There are ample genetic and laboratory studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.

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Targeting PI3K signalling in cancer: opportunities, challenges and limitations.

AKT/PKB (protein kinase B) kinases mediate signaling pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase AKT kinases regulate diverse cellular processes including cell proliferation and survival, cell size and response to nutrient availability, tissue invasion and angiogenesis Many oncoproteins and tumor suppressors implicated in cell signaling/metabolic regulation converge within the AKT signal transduction pathway in an equilibrium that is altered in many human cancers by activating and inactivating mechanisms, respectively, targeting these inter-related proteins We review a burgeoning literature implicating aberrant AKT signaling in many sporadic human cancers as well as in several dominantly inherited cancer syndromes known as phakomatoses The latter include disorders caused by germline mutations of certain tumor suppressor genes, that is, PTEN, TSC2/TSC1, LKB1, NF1, and VHL, encoding proteins that intersect with the AKT pathway We also review various pathogenic mechanisms contributing to activation of the AKT pathway in human malignancy as well as current pharmacologic strategies to target therapeutically components of this pathway

Perturbations of the AKT signaling pathway in human cancer

We investigated the status of the PI 3-kinase/AKT/PTEN signaling pathway in a series of 117 head and neck squamous cell carcinomas (HNSCC) in a search for molecular alterations in genes/proteins with potential prognostic value. For this purpose, PIK3CA and AKT2 gene amplification was assessed by multiplex and Quantitative Real-Time PCR. Protein expression of AKT, p-AKT, p110alpha and PTEN was determined by Western blot. PTEN allelic loss was evaluated by microsatellite analysis. PTEN-exon 5 was screened for point mutations by PCR-SSCP. Homozygous deletions were determined by multiplex PCR. PIK3CA gene was amplified in 43/117 (37%) fresh tumor samples, a frequency that did not differ from that found in archival premalignant tissues: 15/38 (39%); 12/40 (30%) fresh tumors harbored AKT2 gene amplification. AKT was found activated in 6/36 (17%) fresh tumor samples, when compared to their normal tissue counterparts. Of these 6 cases, 1 showed p110alpha overexpression and 5 displayed PTEN protein downregulation. Neither allelic loss (found in 11/77 informative cases) nor point mutations or homozygous deletions accounted for the reduced PTEN protein expression observed in our tumor series. The histologically normal mucosa of 4 patients displayed some of the molecular alterations analyzed. Dysregulation of the PI 3-K/AKT/PTEN pathway might contribute to early HNSCC tumorigenesis and might constitute a potential clinical target. Overall, 17/36 (47%) cases showed at least 1 of the molecular alterations studied here, which makes the PI 3-kinase-initiated signaling pathway one of the most frequently altered in HNSCC.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.20711

Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma.

EGFR, p27kip1 and Skp2, have been implicated in human cancer development. We have studied these molecules in a search for molecular markers that may have prognostic value in head and neck squamous cell carcinomas (HNSCC). Tissue samples of 62 patients were collected and immunohistochemical analysis was carried out for p27kip1, Skp2 and EGFR protein evaluation. Western blot analysis of p27kip1 was performed. The p27kip1 expression is frequently down-regulated in HNSCC (44.4%, 20/45 cases). The immunohistochemical analysis showed p27kip1 cytoplasmic retention in 7/38 tumors. Strong Skp2 signals were detected at the invasive edge of the tumor in cells lacking p27kip1 staining. We found a high EGFR staining in 49% (23/47) of the cases. The staining tended to be more frequent in lymph node-positive cases. The dysplastic tissue exhibited no Skp2 immunoreactivity, whereas 51.06% (24/47) of invasive tumors expressed high levels. Of note is that Skp2 overexpression was the only factor that significantly correlated with a shorter overall survival in multivariate analysis (p=0.048). Our results suggest that Skp2 is a useful prognostic marker for HNSCC management.

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Skp2, p27kip1 and EGFR assessment in head and neck squamous cell carcinoma: Prognostic implications

Background: Molecular events following nicotinic acetylcholine receptor (nAChR) activation by nicotine are poorly understood. The phosphatidylinositol 3-kinase (PI3- K)/Akt/PTEN pathway has been suggested to play a role in the antiapoptotic responses to nicotine. Materials and Methods: To elucidate the possible role of ·3, ·5 and ·7 nAChR subunit mediated PI3-K/Akt/PTEN pathway activation in squamous cell carcinoma of the head and neck (HNSCC) development, mRNA was isolated from 30 HNSCC tissues of known Akt activation state and were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Results: ·3, ·5 and ·7 nAChR subunits were expressed in 1/30 (3.33%), 15/30 (50%) and 10/30 (33.33%), respectively. These results did not correlate with pAkt levels, previously assessed in our laboratory, or any of the clinicopathological parameters considered. Conclusion: This is the first report on nAChR subunit expression in human HNSCC surgical specimens of known pAkt levels. Our results suggest that nAChRs might exert their function through pathways different from PI3-K/Akt/PTEN and that ·3, ·5 or ·7 nAChR subunit expression might not be useful prognostic markers in HNSCC. Squamous cell carcinoma of the head and neck (HNSCC) remains a significant cause of morbidity and mortality, afflicting approximately 500,000 new cases worldwide each year (1). The complex development of HNSCC is thought to progress through a series of well-defined clinical and histopathological stages, which correlate with the accumulation of multiple genetic events (2). The recognized risk factors for head and neck carcinoma (heavy smoking and high alcohol consumption in developed countries) and the clinical appearance of premalignant lesions are poor predictors of risk of tumor development so molecular markers for cancer-risk assessment are needed (3).

Dario Garcia Carracedo

Papers

Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma.

Skp2, p27kip1 and EGFR assessment in head and neck squamous cell carcinoma: Prognostic implications

Epithelial cell nicotinic acetylcholine receptor expression in head and neck squamous cell carcinoma pathogenesis.