Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Proliferating cells, including cancer cells, require altered metabolism to efficiently incorporate nutrients such as glucose into biomass. The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. We demonstrate that phosphoenolpyruvate (PEP), the substrate for pyruvate kinase in cells, can act as a phosphate donor in mammalian cells because PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2-expressing cells. We used mass spectrometry to show that the phosphate from PEP is transferred to the catalytic histidine (His11) on human PGAM1. This reaction occurred at physiological concentrations of PEP and produced pyruvate in the absence of PKM2 activity. The presence of histidine-phosphorylated PGAM1 correlated with the expression of PKM2 in cancer cell lines and tumor tissues. Thus, decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1 and may provide an alternate glycolytic pathway that decouples adenosine triphosphate production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support the anabolic metabolism observed in many proliferating cells.

Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells

Role of epithelial to mesenchymal transition in hepatocellular carcinoma

Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade. Moreover, many metastases display different metabolic traits compared with the tumours from which they originate, enabling survival and growth in the new environment. Consequently, the stage-dependent metabolic traits may provide therapeutic windows for preventing or reducing metastasis, and targeting the new metabolic traits arising in established metastases may allow their eradication.

The metabolism of cancer cells during metastasis.

Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.

Gastric cancer: a comprehensive review of current and future treatment strategies

We determined the expression of epithelial-mesenchymal transition (EMT) indicator proteins, E-cadherin (E-cad), vimentin (VIM), mucin 1 (MUC1) and S100 calcium-binding protein A4 (S100A4) in hepatocellular carcinoma (HCC) patient tissue samples. We also investigated the relationship between the expression of these proteins and clinicopathologic factors in HCC. Finally, we assessed the potential value of these markers as prognostic indicators of survival in HCC patients. The expression of E-cad, VIM, MUC1 and S100A4 EMT indicator proteins was assessed in tissue microarray HCC tissue sections and corresponding peritumoral normal tissues by immunohistochemistry. In addition, the expression for the four EMT indicator proteins was correlated with clinicopathological features of HCC and patient outcome. Comparison of clinicopathological characteristics and immunohistochemistry by χ2 analysis revealed that downregulation of E-cad in HCC was significantly associated with later TNM cancer stage (P = 0.012), gross classification (P = 0.018), regional lymph node metastasis (P = 0.036) and liver cirrhosis (P = 0.028). Increased S100A4 expression in HCC was significantly associated with differentiation (P = 0.032), tumor with a complete fibrous capsule (P = 0.031) and portal vein invasion (P = 0.038). High VIM expression in HCC was significantly associated with high serum α-fetoprotein levels (P = 0.016). We also observed that low E-cad expression was significantly associated with overexpression of VIM (P = 0.001). Kaplan–Meier survival and Cox regression analysis revealed that low E-cad expression (HR = 0.164, 95 % CI 0.072 to 0.373, P < 0.001) and high serum α-fetoprotein levels (HR = 2.202, 95 % CI 1.054 to 4.598, P = 0.036) were independent prognostic factors in HCC. Our study demonstrates that high S100A4 and VIM expression and low E-cad expression correlate with an aggressive, malignant phenotype in HCC. These results also support a role for E-cad as a prognostic factor in HCC.

Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC

Fatty acid binding proteins (FABPs) are intracellular lipid-binding proteins that are involved in a variety of biological cellular processes, including tumorigenesis. In this study, we explored the expression pattern of FABP3 and FABP4 in non-small cell lung cancer (NSCLC) as well as their roles in prognosis. We determined mRNA expression of FABP3 and FABP4 in matched pairs of cancerous and non-cancerous fresh frozen tissues from 30 NSCLC patients. Tissue microarray immunohistochemical analysis (TMA-IHC) was applied to determine the protein expression of FABP3 and FABP4 in 281 cancerous and 121 matched adjacent non-cancerous tissue samples. Our results showed that both mRNA and protein expression of FABP3 and FABP4 were significantly higher in cancerous tissues when compared to non-cancerous tissues. Furthermore, high expression of FABP3 or FABP4 in NSCLC was significantly associated with advanced tumor node metastasis (TNM) stage and had a negative impact on the overall survival of NSCLC patients. Concurrent high expression of FABP3 and FABP4 was significantly related to TNM stage. In conclusion, our research demonstrated that high FABP3 or FABP4 expression had strong prognostic value for overall survival in NSCLC. Detection of FABP3 and FABP4 cooperatively was helpful to predict the prognosis of NSCLC.

Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC).

Lysosomal associated membrane protein 3 (LAMP3) is a newly identified tumor-specific protein. It is a downstream target gene of tumor suppressor TP53 and its expression has been associated with hypoxia-induced metastasis and poor overall survival in cervical and breast cancers. However, little is known of LAMP3 protein expression in gastrointestinal cancer and its prognostic value. We determined protein expression of LAMP3 and TP53 in both gastric (n=750) and colorectal (n=479) tissues by immunohistochemistry analysis on tissue microarray (TMA), their expression was correlated with patients' clinical parameters. LAMP3 and TP53 protein expression was significantly higher in cancerous tissues compared to normal and benign tissues. In both gastric and colorectal cancers, high LAMP3 protein expression (LAMP3+) was significantly associated with tumor stage (P=0.014 and P<0.001). No correlation between LAMP3 and TP53 expression was observed. Patients with high LAMP3 expression but not high TP53 expression had a poor overall survival (for gastric cancer P<0.001, CI: 1.762-4.567; for colorectal cancer P=0.036, CI: 1.062-5.980). Our data suggest that epithelial LAMP3 expression is an independent prognostic marker for gastrointestinal cancer.

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Prognostic value of LAMP3 and TP53 overexpression in benign and malignant gastrointestinal tissues.

Increased Expression of PHGDH and Prognostic Significance in Colorectal Cancer

The cell surface protein Trop2 is overexpressed in a variety of human cancers. Trop2 expression increases tumor development and metastasis and reduces patient survival. However, little is known about the role of Trop2 expression and its prognostic value in gastric cancer (GC), particularly in Chinese populations. We analyzed Trop2 expression in GC tissues collected from Chinese GC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry on tissue microarrays were performed to assess levels of Trop2 mRNA and protein in GC, and correlations between Trop2 expression and clinical characteristics and prognosis were analyzed. Trop2 expression was higher in GC tissues than in neighboring non-tumor tissues. Increased Trop2 protein levels in GC were associated with increased differentiation, tumor node metastasis stage, tumor size, lymph node metastasis, distant metastasis, and H. pylori infection. GC patients with high Trop2 expression also had poor overall survival rates. These data suggest Trop2 is a useful prognostic biomarker for GC.

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Wei Wang

Papers

Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC

Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC).

Prognostic value of LAMP3 and TP53 overexpression in benign and malignant gastrointestinal tissues.

Increased Expression of PHGDH and Prognostic Significance in Colorectal Cancer

Trop2 is overexpressed in gastric cancer and predicts poor prognosis.