J. M. Price

Naturally Occurring and Bracken-Fern-Induced Bovine Urinary Bladder Tumors Clinical and Morphological Characteristics

Clinical and morphological characteristics of 139 naturally occurring and 20 bracken-fern-induced urinary bladder tumors of cows were studied. Hematuria was prominent and occurred as early as 60 days after bracken fern feeding began. Anemia and changes in leukocytes were late manifestations. Papillomas appeared as early as 1 year, whereas invasive carcinomas did not develop until 2.6 years after initiation of feeding. Twenty of 30 cows fed bracken fern developed bladder tumors within 5.3 years. None of eight untreated control cows that lived 4 years or six that lived 10 years developed neoplasms. Naturally occurring and fern-induced bladder tumors were epithelial (35%) or mixed epithelial and stromal (55%). Papillomas occurred in 24% and carcinomas in 61% of naturally occurring cases, whereas there were papillomas (40%) and carcinomas (50%) in fern-fed cows. Naturally occurring tumors were metastatic to regional lymph nodes and lung. No metastases were detected in fern-fed cows.Clinical and morphological characteristics of 139 naturally occurring and 20 braken-fern-induced urinary bladder tumors of cows were studied. Hematuria was prominent and occurred as early as 60 days after braken fern feeding began. Anemia and changes in leukocytes were late manifestations. Papillomas appeared as early as 1 year, whereas invasive carcinomas did not develop until 2.6 years after initiation of feeding. Twenty of 30 cows fed braken fern developed bladder tumors within 5.3 years. None of eight untreated control cows that lived 4 years or six that lived 10 years developed neoplasms. Naturally occurring and fern-induced bladder tumors were epithelial (35%) or mixed epithelial and stromal (55%). Papillomas occurred in 24% and carcinomas in 61% of naturally occurring cases, whereas there were papillomas (40%) and carcinomas (50%) in fern-fed cows. Naturally occurring tumors were metastatic to regional lymph nodes and lung. No metastases were detected in fern-fed cows.

Insulin growth factor 1 like receptor (IGF-1R).

BackgroundThe epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood.MethodsIn this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab. Co-immunoprecipitation, small molecule inhibitors against phospho-Src and IGF-1R, quantitative western blot of EGFR and Src phosphorylation, cell proliferation assays were used to suggest the role of IGF-1R mediated phosphorylation of specific tyrosine Y845 on EGFR via increased heterodimerization of EGFR and IGF-1R in cetuximab resistant cells.ResultsHeterodimerization of EGFR with IGF-1R was increased in cetuximab resistant HNSCC cell line UMSCC6. Basal levels of phosphorylated EGFR Y845 showed significant increase in the presence of cetuximab. Surprisingly, this activated Y845 level was not inhibited in the presence of Src inhibitor PP1. Instead, inhibition of IGF-1R by picropodophyllin (PPP) reduced the EGFR Y845 levels. Taken together, these results suggest that heterodimerization of EGFR with IGF-1R can lead to increased activity of EGFR and may be an important platform for cetuximab mediated signaling in head and neck tumors that have become resistant to anti-EGFR therapy.ConclusionsEGFR-IGF-1R interaction has a functional consequence of phosphorylation of EGFR Y845 in cetuximab resistant HNSCC cells and dual targeting of EGFR and IGF-1R is a promising therapeutic strategy.

Erratum to: Insulin-like growth factor 1 receptor mediated tyrosine 845 phosphorylation of epidermal growth factor receptor in the presence of monoclonal antibody cetuximab

BACKGROUND The epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood. METHODS In this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab. Co-immunoprecipitation, small molecule inhibitors against phospho-Src and IGF-1R, quantitative western blot of EGFR and Src phosphorylation, cell proliferation assays were used to suggest the role of IGF-1R mediated phosphorylation of specific tyrosine Y845 on EGFR via increased heterodimerization of EGFR and IGF-1R in cetuximab resistant cells. RESULTS Heterodimerization of EGFR with IGF-1R was increased in cetuximab resistant HNSCC cell line UMSCC6. Basal levels of phosphorylated EGFR Y845 showed significant increase in the presence of cetuximab. Surprisingly, this activated Y845 level was not inhibited in the presence of Src inhibitor PP1. Instead, inhibition of IGF-1R by picropodophyllin (PPP) reduced the EGFR Y845 levels. Taken together, these results suggest that heterodimerization of EGFR with IGF-1R can lead to increased activity of EGFR and may be an important platform for cetuximab mediated signaling in head and neck tumors that have become resistant to anti-EGFR therapy. CONCLUSIONS EGFR-IGF-1R interaction has a functional consequence of phosphorylation of EGFR Y845 in cetuximab resistant HNSCC cells and dual targeting of EGFR and IGF-1R is a promising therapeutic strategy.