Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Kim, Edward S.; Liu, Diane; Lee, J. Jack; Solis, Luisa M.; Behrens, Carmen; Lippman, Scott M.; Hong, Waun Ki; Wistuba, Ignacio I.; Lee, Ho‐Young

doi:10.1002/cncr.26492

Cited by 53 publications

(53 citation statements)

References 36 publications

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“…NSCLC expresses the insulin receptor, and high levels of insulin receptor expression have been associated with faster cancer progression and decreased survival (35). Metformin reduces insulin resistance and circulating insulin levels, thereby attenuating the stimulatory effect of insulin (36).…”

Section: Discussionmentioning

confidence: 99%

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Lin

Gallagher

Sigel

et al. 2015

Am J Respir Crit Care Med

120

106

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Rationale: Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer.Objectives: To compare overall survival of patients with diabetes with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin.Methods: Using data from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 750 patients with diabetes 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders.Measurements and Main Results: Overall, 61% of patients were on metformin at the time of lung cancer diagnosis. Median survival in the metformin group was 5 months, compared with 3 months in patients not treated with metformin (P , 0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio, 0.80; 95% confidence interval, 0.71-0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment.Conclusions: Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect. Further research should evaluate plausible biologic mechanisms and test the effect of metformin in prospective clinical trials.

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Section: Discussionmentioning

confidence: 99%

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Lin

Gallagher

Sigel

et al. 2015

Am J Respir Crit Care Med

120

106

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“…Previous studies have reported that high expression level of IGF-IR was associated with poor survival of patients with various types of cancer (10). Up to date, limited data exist on clinical significance of IGF-IR expression in lung cancer, and the association between IGF-IR and poor prognosis remains controversy (27,28). In this study, we found that IGF-IR could mediate the formation of a novel b-catenin/POU5F1/SOX2 complex in LACSLCs to play a crucial role in self-renewal of lung cancer cells and predict poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin/POU5F1/SOX2 Transcription Factor Complex Mediates IGF-I Receptor Signaling and Predicts Poor Prognosis in Lung Adenocarcinoma

Xie

et al. 2013

Cancer Research

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Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3b/b-catenin cascade. POU5F1 could form a novel complex with b-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with b-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with b-catenin and SOX2 is crucial for the selfrenewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, b-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma.

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“…In breast cancer, a high level of IR expression is indicative of poor survival [92,93]. Overexpression of IR predicts poor survival also in patients with nonsmall cell lung cancer [94]. The interpretation of these data is complicated because circulating insulin levels were not reported.…”

Section: Insulin Receptors As Prognostic Markers In Cancermentioning

confidence: 99%

Insulin, insulin receptors, and cancer

Vigneri

Goldfine

Frittitta

2016

J Endocrinol Invest

185

147

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Insulin is a major regulator of cell metabolism but, in addition, is also a growth factor. Insulin effects in target cells are mediated by the insulin receptor (IR), a transmembrane protein with enzymatic (tyrosine kinase) activity. The insulin receptor, however, is represented by a heterogeneous family of proteins, including two different IR isoforms and also hybrid receptors resulting from the IR hemireceptor combination with a hemireceptor of the cognate IGF-1 receptor. These different receptors may bind insulin and its analogs with different affinity and produce different biologic effects. Since many years, it is known that many cancer cells require insulin for optimal in vitro growth. Recent data indicate that: (1) insulin stimulates growth mainly via its own receptor and not the IGF-1 receptor; (2) in many cancer cells, the IR is overexpressed and the A isoform, which has a predominant mitogenic effect, is more represented than the B isoform. These characteristics provide a selective growth advantage to malignant cells when exposed to insulin. For this reason, all conditions of hyperinsulinemia, both endogenous (prediabetes, metabolic syndrome, obesity, type 2 diabetes before pancreas exhaustion and polycystic ovary syndrome) and exogenous (type 1 diabetes) will increase the risk of cancer. Cancer-related mortality is also increased in patients exposed to hyperinsulinemia but other factors, related to the different diseases, may also contribute. The complexity of the diseases associated with hyperinsulinemia and their therapies does not allow a precise evaluation of the cancer-promoting effect of hyperinsulinemia, but its detrimental effect on cancer incidence and mortality is well documented.

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Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Cited by 53 publications

References 36 publications

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

β-Catenin/POU5F1/SOX2 Transcription Factor Complex Mediates IGF-I Receptor Signaling and Predicts Poor Prognosis in Lung Adenocarcinoma

Insulin, insulin receptors, and cancer

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