Serum Levels of Insulin Growth Factor (IGF-I) and IGF-Binding Protein Predict Risk of Second Primary Tumors in Patients with Head and Neck Cancer

Wu, Xifeng; Zhao, Hua; Anh, Kim; Johnson, Marcella M.; Dong, Qiong; Hong, Waun Ki; Spitz, Margaret R.

doi:10.1158/1078-0432.ccr-03-0762

Cited by 64 publications

(42 citation statements)

References 50 publications

(46 reference statements)

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“…Many studies have shown that elevated serum IGF-I levels are associated with increased risks for a variety of cancers (32 -35). A recent study on a subset of patients with head and neck cancer from the current study population showed that elevated IGF-I levels were associated with a significantly increased risk of subsequent development of SPTs (36).…”

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confidence: 54%

Joint Effect of Mutagen Sensitivity and Insulin-Like Growth Factors in Predicting the Risk of Developing Secondary Primary Tumors and Tumor Recurrence in Patients with Head and Neck Cancer

Gu²,

Dong

et al. 2006

Clinical Cancer Research

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Purpose: Early-stage head and neck cancer patients are at high risks for tumor recurrence and secondary primary tumor (SPT) development.We hypothesized that latent genetic instability and proliferation potential may be associated with elevated risks of SPTand recurrence. Experimental Design: We conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage head and neck cancer. We compared prediagnostic bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures (as an indicator of latent genetic instability) between 298 cases (patients with SPT/recurrence) and 693 controls (patients without SPT/recurrence). We also determined the joint effects of latent genetic instability and elevated proliferation potential [indicated by serum insulin-like growth factor (IGF) level] in modulating the risk of SPTand recurrence. Results: In the Cox proportional hazards model, patients with higher mutagen sensitivity (using a cutoff of z0.50 breaks per cell) exhibited a significantly increased risk of developing SPT/ recurrence [hazard ratio, 1.38; 95 % confidence interval (95 % CI), 1.02-1.86]. Cases also exhibited significantly higher levels of IGF-I and IGF-binding protein-3 than controls (P = 0.022 and 0.042, respectively). Moreover, there were joint effects between mutagen sensitivity and IGFs in modulating SPT/recurrence risk. Using patients with low IGF-I level and low mutagen sensitivity profile as the reference group, the odds ratios of developing SPT/recurrence for patients with high IGF-I level alone, high mutagen sensitivity alone, and both high IGF-I level and high mutagen sensitivity were 2.85 (95% CI, 0.92-8.82), 3.92 (95% CI, 1.28-11.97), and 6.16 (95% CI, 2.03-18.71), respectively. A similar joint effect was observed for mutagen sensitivity and IGF-binding protein-3 level. Conclusions:This is the largest prospective study to evaluate mutagen sensitivity as a prognosis marker in head and neck cancer because mutagen sensitivity data were derived from baseline samples drawn before the development of SPT or tumor recurrence. The results also show for the first time that latent genetic instability and elevated proliferation potential jointly elevate the risk of second tumors in early-stage head and neck cancers.Head and neck cancer (including malignancies in the oral cavity, pharynx, and larynx) will occur with an estimated incidence of 40,500 new cases (22,040 in oral cavity, 8,950 in pharynx, and 9,510 in larynx) and cause f11,170 deaths in the United States in 2006 (1). Cigarette smoking and alcohol consumption are the predominant risk factors for head and neck cancer, estimated to be responsible for three fourths of all the cases (2). However, only a small fraction of smokers and drinkers develop these cancers, suggesting that variations in genetic susceptibility may play important roles in cancer etiology. There have been numerous studies supporting this concept, including evidence of increased risk of head and neck cancer ...

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confidence: 54%

Joint Effect of Mutagen Sensitivity and Insulin-Like Growth Factors in Predicting the Risk of Developing Secondary Primary Tumors and Tumor Recurrence in Patients with Head and Neck Cancer

Gu²,

Dong

et al. 2006

Clinical Cancer Research

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“…IGFBP-3 has been also identified as having antitumor activities in a variety of cancers (16,44,45). Several case control studies have shown that serum IGFBP-3 levels inversely correlate with the risk of numerous cancers, including prostate (46), bladder (46), and colon (46). Smoking reduces IGFBP-3 levels (46) and low GAPDH mRNA and h-actin protein expression were also detected as controls for reverse transcription-PCR and Western blot analyses, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…(24). Furthermore, a decrease in IGFBP-3 expression due to the methylation or polymorphisms of the IGFBP-3 promoter is associated with an increased risk of lung, breast, and prostate cancers (46). Considering all of these promising results, IGFBP-3 should be critically evaluated in translational clinical trials against pathologic angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma

Oh¹,

Kim²,

Kim³

et al. 2006

Clinical Cancer Research

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The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.

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“…A renewed interest in the role of the IGF system in cancer has surfaced over the past few years with IGF-1/2 having been identified as risk factors in breast, prostate, colon, cervical (Voskuil et al, 2005), and head and neck cancers (Wu et al, 2004). Accompanied by this is the observation that IGFBP-3 is a negative risk factor for cancer (Rosenzweig, 2004).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor Binding Protein-2: Contributions of the C-Terminal Domain to Insulin-Like Growth Factor-1 Binding

Kibbey

Jameson²,

Eaton³

et al. 2005

Mol Pharmacol

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Signaling by the insulin-like growth factor (IGF)-1 receptor (IGF-1R) has been implicated in the promotion and aggressiveness of breast, prostate, colorectal, and lung cancers. The IGF binding proteins (IGFBPs) represent a class of natural IGF antagonists that bind to and sequester IGF-1/2 from the IGF-1R, making them attractive candidates as therapeutics for cancer prevention and control. Recombinant human IGFBP-2 significantly attenuated IGF-1-stimulated MCF-7 cell proliferation with coaddition of 20 or 100 nM IGFBP-2 (50 or 80% inhibition, respectively). We previously identified IGF-1 contact sites both upstream and downstream of the CWCV motif (residues 247-250) in human IGFBP-2 (J Biol Chem 276: 2880 -2889, 2001). To further test their contributions to IGFBP-2 function, the single tryptophan in human IGFBP-2, Trp-248, was selectively cleaved with 2-(2Јnitrophenylsulfenyl)-3-methyl-3 bromoindolenine (BNPS-skatole) and the BNPS-skatole products IGFBP-2 1-248 and IGFBP-2 249 -289 as well as IGFBP-2 1-190 were expressed as glutathione S-transferase-fusion proteins and purified. Based on competition binding analysis, deletion of residues 249 to 289 caused an ϳ20-fold decrease in IGF-1 binding affinity (IGFBP-2 EC 50 ϭ 0.35 nM and IGFBP-2 1-248 ϭ 7 nM). Removal of the remainder of the C-terminal domain had no further effect on affinity (IGFBP-2 1-190 EC 50 ϭ 9.2 nM). In kinetic assays, IGFBP-2 1-248 and IGFBP-2 1-190 exhibited more rapid association and dissociation rates than full-length IGFBP-2. These results confirm that regions upstream and downstream of the CWCV motif participate in IGF-1 binding. They further support the development of full-length IGFBP-2 as a cancer therapeutic.

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Serum Levels of Insulin Growth Factor (IGF-I) and IGF-Binding Protein Predict Risk of Second Primary Tumors in Patients with Head and Neck Cancer

Cited by 64 publications

References 50 publications

Joint Effect of Mutagen Sensitivity and Insulin-Like Growth Factors in Predicting the Risk of Developing Secondary Primary Tumors and Tumor Recurrence in Patients with Head and Neck Cancer

Joint Effect of Mutagen Sensitivity and Insulin-Like Growth Factors in Predicting the Risk of Developing Secondary Primary Tumors and Tumor Recurrence in Patients with Head and Neck Cancer

Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma

Insulin-Like Growth Factor Binding Protein-2: Contributions of the C-Terminal Domain to Insulin-Like Growth Factor-1 Binding

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