atrial-natriuretic-factor and Carcinoma--Squamous-Cell

The natriuretic peptide (NP) system comprises of three ligands, the Atrial Natriuretic Peptide (ANP), Brain Natriuretic peptide (BNP) and C-type Natriuretic peptide (CNP), and three natriuretic peptide receptors, NPRA, NPRB and NPRC. Here we present a comprehensive study of the natriuretic peptide system in healthy murine and human submandibular salivary glands (SMGs). We show CNP is the dominant NP in mouse and human SMG and is expressed together with NP receptors in ducts, autonomic nerves and the microvasculature of the gland, suggesting CNP autocrine signalling may take place in some of these glandular structures. These data suggest the NP system may control salivary gland function during homeostasis through the regulation of electrolyte re-absorption, neural stimulation and/or blood vessel wall contraction/relaxation. We also show abnormal expression of NPRA in the stroma of a subset of human SMGs resected from patients diagnosed with oral squamous cell carcinoma (OSCC) of non-salivary gland origin. This finding warrants further research to investigate a possible correlation between early OSCC invasion and NPRA overexpression.

Topics: Animals; Atrial Natriuretic Factor; Carcinoma, Squamous Cell; Female; Humans; Male; Mice; Mouth Neoplasms; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neoplasm Proteins; Receptors, Peptide; Submandibular Gland

VILIP-1 (visinin-like protein 1) is downregulated in various human squamous cell carcinoma (SCC). In a mouse skin SCC model VILIP-1 expression is reduced in aggressive tumor cells, accompanied by reduced cAMP levels. Overexpression of VILIP-1 in aggressive SCC cells led to enhanced cAMP production, in turn causing a reduction in invasive properties. Moreover, in primary neurons and neuronal tumor lines VILIP-1 enhanced cGMP signaling. Here, we set out to determine whether and how cAMP and cGMP signaling contribute to the VILIP-1 effect on enhanced SCC model cell migration, and thus most likely invasiveness in vivo. We found stronger increase in cGMP levels in aggressive, VILIP-1-negative SCC cells following stimulation of guanylyl cyclases NPR-A and -B with the natriuretic peptides ANP and CNP, respectively. Incubation with ANP or 8Br-cGMP to increase cGMP levels further enhanced the migration capacity of aggressive cells, whereas cell adhesion was unaffected. Increased cGMP was caused by elevated expression levels of NPR-A and -B. However, the expression level of VILIP-1 did not affect cGMP signaling and guanylyl cyclase expression in SCC. In contrast, VILIP-1 led to reduced migration of aggressive SCC cells depending on cAMP levels as shown by use of adenylyl cyclase (AC) inhibitor 2',3'-dideoxyadenosine. Involvement of cAMP-effectors PKA and EPAC play a role downstream of AC activation. VILIP-1-positive and -negative cells did not differ in mRNA expression of ACs, but an effect on enhanced protein expression and membrane localization of ACs was shown to underlie enhancement of cAMP production and, thus, reduction in cell migration by VILIP-1.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Atrial Natriuretic Factor; Blotting, Western; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cyclic AMP; Cyclic GMP; Dideoxyadenosine; Guanosine Monophosphate; Humans; Mice; Microscopy, Fluorescence; Neurocalcin; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Skin Neoplasms

Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, have anticancer effects in vitro.. These cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 0.3 nM kg(-1) body weight in athymic mice bearing human squamous cell carcinomas.. Vessel dilator, atrial natriuretic peptide and kaliuretic peptide each eliminated one in six (17%) of the human squamous cell lung carcinomas. Long-acting natriuretic peptide, although it did not eliminate any of the human squamous cell lung carcinomas did decrease the volume of one carcinoma to only 2% (P < 0.0001) of the untreated carcinomas. The squamous cell lung carcinomas that were not eliminated, with the exception of the one LANP-treated tumour that decreased to only 2% of the volume of the untreated cancers, grew rapidly but their growth velocity compared to controls decreased by 76%, 40%, 38% and 25% in the vessel dilator, atrial natriuretic peptide, kaliuretic peptide and long-acting natriuretic peptide groups respectively (P < 0.05).. Three of four cardiac hormones synthesized by the atrial natriuretic peptide gene can eliminate human squamous cell lung carcinomas in athymic mice when treated subcutaneously for 4 weeks. The 4th cardiac hormone, i.e. long-acting natriuretic peptide, decreased the volume of one squamous cell lung carcinoma to 2% of that of untreated animals, suggesting that it, too, has beneficial effects on squamous cell lung cancers.

Topics: Animals; Antineoplastic Agents; Atrial Natriuretic Factor; Carcinoma, Squamous Cell; Cell Line, Tumor; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Peptide Fragments; Tumor Cells, Cultured

Within 24 h four peptide hormones, i.e. vessel dilator, long acting natriuretic peptide, kaliuretic peptide, and atrial natriuretic peptide and their intracellular mediator cyclic GMP decreased the number of human squamous lung cancer cells 51, 22, 25, 21, and 30%, respectively. There was not any proliferation in the 3 days following this decrease in cell number. Vessel dilator decreased DNA synthesis 85% in the squamous lung cancer cells. Thus, vessel dilator significantly decreased the number of human squamous lung cancer cells and their DNA synthesis, mediated in part by cyclic GMP, more than other peptide hormones.

Topics: Atrial Natriuretic Factor; Carcinoma, Squamous Cell; Cell Proliferation; Cyclic GMP; DNA Replication; DNA, Neoplasm; Humans; Lung Neoplasms; Peptide Fragments; Protein Precursors; Tumor Cells, Cultured

To test the hypothesis that neural mechanisms evoked by unilateral pulmonary artery occlusion (UPAO) affect the release of atrial natriuretic peptides (ANP) from the heart, hemodynamics and levels of plasma ANP and cyclic guanosine monophosphate (c-GMP) were studied in 11 patients with lung cancer. The UPAO induced a significant rise in heart rate by 5.3 percent, increased mean pulmonary artery pressure by 31 percent without affecting right atrial pressure, and decreased plasma ANP levels in the coronary sinus by 17.4 percent (p < 0.05) from 202.5 +/- 27.1 pg/ml to 167.2 +/- 27.4 pg/ml. Atropine sulfate (0.04 mg/kg) injection increased the heart rate by 38.2 percent (p < 0.01), reduced the stroke volume index by 25.1 percent, decreased coronary sinus ANP levels from 198.5 +/- 16.4 pg/ml to 124.8 +/- 19.6 pg/ml (p < 0.01), and decreased coronary sinus plasma c-GMP levels from 4.6 +/- 0.5 pmol/ml to 3.1 +/- 0.4 pmol/ml (p < 0.05). After atropine pretreatment, UPAO induced a significant (p < 0.05) increase of 34.8 percent in the coronary sinus ANP level. Thus, it is concluded that in UPAO, the secretion of ANP from the heart is modulated partly by the autonomic nervous system.

Topics: Adenocarcinoma; Aged; Atrial Natriuretic Factor; Atropine; Carcinoma, Squamous Cell; Catheterization, Peripheral; Cyclic GMP; Female; Heart; Hemodynamics; Humans; Lung Neoplasms; Male; Middle Aged; Pulmonary Artery; Time Factors

Atrial natriuretic factor is a new peptide hormone synthesized in the heart which has potent natriuretic, diuretic, and vasodilatory properties. A 47-year-old man with squamous cell carcinoma of the lung resected 6 months previously presented with syncope secondary to hypotension and a low serum sodium. He was evaluated to determine if atrial natriuretic factor (ANF) might be the etiology of this clinical picture. His plasma concentration of atrial natriuretic factor was increased three-fold over that of 70 normotensive person. Further evaluation revealed metastatic lesions in the right and left cardiac atria with the mass on the left occluding 75% of the left atrial chamber. The mass effect in the atria increasing atrial stretch and atrial pressure one would expect was the main contributor to the increased ANF level. The contribution of direct tumor invasion into the atria and/or production of atrial natriuretic factor by the tumor itself to produce this elevated plasma level of atrial natriuretic factor could not be determined, but this markedly elevated level of atrial natriuretic factor does appear to be the etiology of this patient's clinical picture.

Topics: Atrial Natriuretic Factor; Biomarkers, Tumor; Carcinoma, Squamous Cell; Echocardiography; Heart Atria; Heart Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Radioimmunoassay