Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer

Yip, Po Yee; Cooper, Wendy A.; Kohonen‐Corish, Maija; Lin, Betty; McCaughan, Brian C.; Boyer, Michael; Kench, James G.; Horvath, Lisa G.

doi:10.1136/jclinpath-2013-201870

Cited by 8 publications

(4 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(27) Recently, it was described that cases expressing nuclear p-Akt showed a poorer prognosis. (28) Nonetheless, other investigators have suggested that cancers expressing p-Akt in the nucleus have a better prognosis and responded better to targeted therapy. (19) Analytical methods have recently been further refined due to the development of commercially available isoform-specific or phosphorylated-form-specific antibodies applicable to IHC on paraffin-embedded tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies found that expression of p‐Akt was not associated with prognosis, and was even associated with longer survival, but other studies showed a poorer prognosis . Recently, it was described that cases expressing nuclear p‐Akt showed a poorer prognosis . Nonetheless, other investigators have suggested that cancers expressing p‐Akt in the nucleus have a better prognosis and responded better to targeted therapy .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas

et al. 2015

View full text Add to dashboard Cite

Emerging evidence confirms a central role of Akt in cancer. To evaluate the relative contribution of deregulated Akt and their clinicopathological significance in lung carcinomas, overexpression, activation of Akt and AKT gene increases were investigated. Immunohistochemical staining for 108 cases revealed overexpression of total Akt, Akt1, Akt2 and Akt3 in 61.1, 47.2, 40.7 and 23.1%, respectively, and phosphorylated Akt in 42.6% of cases. Expression of total Akt, Akt2 and Akt3 were frequently observed in small cell carcinoma, but phosphorylated Akt and Akt1 were more frequently observed in squamous cell carcinoma. FISH analysis to evaluate gene increases of AKT1-3 revealed amplification of AKT1 in 4.2% and AKT1 increase by polysomy of chromosome 14 in 27.3% of cases. For AKT2, amplification was observed in 3.2% and polysomy of chromosome 19 in 26.3% of cases. AKT3 increase was observed in 40.0% of cases only by polysomy of chromosome 1. Although “FISH-positive” AKT1 and AKT2 gene increases (amplification/high-level polysomy) were found exclusively in the cases overexpressing total Akt, Akt1 or Akt2, respectively, AKT3 increase was irrelevant of Akt3 expression. Statistically, expressions of Akt2, p-Akt and cytoplasmic-p-Akt were correlated with lymph node metastasis (P = 0.0479, P = 0.0371 and P = 0.0310, respectively). Although AKT1 and AKT2 gene increase showed positive correlation with, or trend towards a positive correlation with tumor size (P = 0.0430, P = 0.0590, respectively), AKT3 did not. In conclusion, Akt isoforms are differentially involved in the pathological phenotype of lung carcinoma in a diverse manner. Because abnormality of Akt1/AKT1 and Akt2/AKT2 correlated with clinicopathological profiles, Akt1/2-specific targeting may open a novel therapeutic window for the group showing Akt deregulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Interestingly, in renal cell carcinoma, Pantuck et al found that high nuclear p-AKT expression was associated with a favorable prognosis, while high cytoplasmic p-AKT expression was associated with a poor prognosis [92]. Conversely, a study in patients with non-small cell lung cancer observed that higher levels of cytoplasmic p-AKT had a trend toward longer overall survival; whereas higher levels of nuclear p-AKT had a poorer prognosis [93]. In general, investigators have identified an association between ERK activation and poor prognosis such as aggressive neoplastic features, metastasis, and reduced survival [94,95].…”

Section: Leptin Biology and Molecules Of Relevant Signal Transductmentioning

confidence: 99%

The potential role of leptin in tumor invasion and metastasis

Ray

Cleary

2017

Cytokine & Growth Factor Reviews

114

View full text Add to dashboard Cite

The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin’s association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin’s potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

show abstract

“…Several clinical studies have revealed that lymphatic invasion is more frequently observed in cancers with higher leptin expression in different tumor types. [9][10][11] There is growing evidence that leptin enhances invasion and metastasis in breast, ovarian, lung, gallbladder, and pancreatic cancers, etc. [12][13][14][15][16] In our previous study, we demonstrated that leptin is upregulated in migration-prone cell lines, and exogenous leptin also enhances the migration ability of glioma cells.…”

Section: Introductionmentioning

confidence: 99%

Induction of osteoclast-like cell formation by leptin-induced soluble intercellular adhesion molecule secreted from cancer cells

Tsai

Chen

et al. 2019

Ther Adv Med Oncol

View full text Add to dashboard Cite

Background: Leptin is considered a tumorigenic adipokine, suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported as proportional to cancer stage and considered as a potential diagnosis biomarker. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. Material and methods: The expression of ICAM-1 and its regulatory signaling were examined by Western blot or flow cytometry. The effect of soluble ICAM-1 on osteoclast formation was investigated by tartrate-resistance acid phosphatase staining of RAW cells and tumor-induced osteolysis in vivo. Results: In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with the receptor activator of nuclear factor kappa-B ligand (RANKL) in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis in vivo. Conclusion: These findings suggest that soluble ICAM-1 produced under leptin treatment enhances osteoclast formation and is involved in tumor-induced osteolysis. Leptin plays an important role in physiology in health and diseases. Leptin affects immune responses that may induce inflammation and carcinogenesis. Leptin is also considered as a tumorigenic adipokine suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported to be proportional to cancer stage and considered as a potential diagnosis biomarker. It has been reported that soluble ICAM-1 allows tumor cells to escape from immune recognition and stimulates angiogenesis and tumor growth. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with receptor activator of nuclear factor-kappa B ligand in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis in vivo. These findings suggest that soluble ICAM-1 produced under leptin treatment is possibly involved in lung and breast cancer bone metastasis.

show abstract

Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer

Abstract: Level of expression of pAkt in the cytoplasm and nucleus is an independent prognostic factor that may help to select patients with high-risk disease.

Cited by 8 publications

References 33 publications

Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas

Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas

The potential role of leptin in tumor invasion and metastasis

Induction of osteoclast-like cell formation by leptin-induced soluble intercellular adhesion molecule secreted from cancer cells

Contact Info

Product

Resources

About