cyclic-gmp and Peritoneal-Neoplasms

The natriuretic effect of atrial natriuretic peptide (ANP) is blunted in certain clinical disorders such as congestive heart failure and liver cirrhosis, despite the elevated plasma ANP levels. These sodium-retaining states are characterized by increased activity of the renal sympathetic nerves. Recent studies have shown higher levels of circulating and urinary catecholamines in cancer patients. We hypothesized that the increased adrenergic activity may be responsible for ascites formation in patients with peritonitis carcinomatosa (PC). The objective of this study was to determine the renal responses to endogenous ANP in patients with PC. Patients, hospitalized at our institute for PC, were examined using renal clearance studies for 2 h. Non-cancer patients were also examined as control subjects. Statistical analysis was performed using Wilcoxon's rank sum test. The results showed that absolute and fractional sodium excretions were markedly lower in patients with PC (54 +/- 16 microEq/min, means +/- SE, p < 0.0005; 0.55 +/- 0.15%, p < 0.005) than in control patients (166 +/- 14 microEql/min; 1.14 +/- 0.09%, respectively). Plasma ANP concentration was increased in patients with PC (34.7 +/- 8.4 pg/ml, p < 0.001) in comparison with control patients (13.3 +/- 2.0 pg/ml). Plasma and urinary levels of norepinephrine were significantly higher in cancer patients (0.36 +/- 0.10 ng/ml, p < 0.05; 125 +/- 20 ng/dl GF, p < 0.05) than in the controls (0.17 +/- 0.02 ng/ml; 73 +/- 13 ng/dl GF). These results suggest that increased renal sympathetic nerve activity may contribute to the attenuation of the natriuretic effect of ANP in patients with PC.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cachexia; Cyclic GMP; Female; Guanosine; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Natriuresis; Norepinephrine; Peritoneal Neoplasms; Peritonitis; Sodium

Matrix metalloproteinase-9 (MMP-9) produced by colorectal cancer cells is a critical determinant of metastatic disease progression and an attractive target for antimetastatic strategies to reduce colon cancer mortality. Cellular signaling by cyclic GMP (cGMP) regulates MMP-9 dynamics in various cell systems, and the bacterial enterotoxin receptor guanylyl cyclase C (GCC), the principle source of cGMP in colonocytes, which is overexpressed in colorectal cancers, inhibits tumor initiation and progression in the intestine. Here, we show that ligand-dependent GCC signaling through cGMP induces functional remodeling of cancer cell MMP-9 reflected by a compartmental redistribution of this gelatinase, in which intracellular retention resulted in reciprocal extracellular depletion. Functional remodeling of MMP-9 by GCC signaling reduced the ability of colon cancer cells to degrade matrix components, organize the actin cytoskeleton to form locomotory organelles and spread, and hematogenously seed distant organs. Of significance, GCC effects on cancer cell MMP-9 prevented establishment of metastatic colonies by colorectal cancer cells in the mouse peritoneum in vivo. Because endogenous hormones for GCC are uniformly deficient in intestinal tumors, reactivation of dormant GCC signaling with exogenous administration of GCC agonists may represent a specific intervention to target MMP-9 functions in colon cancer cells. The notion that GCC-mediated regulation of cancer cell MMP-9 disrupts metastasis, in turn, underscores the unexplored utility of GCC hormone replacement therapy in the chemoprevention of colorectal cancer progression.

Topics: Caco-2 Cells; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Cyclic GMP; Epithelial Cells; Guanylate Cyclase; Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasm Metastasis; Peritoneal Neoplasms; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction

Topics: Animals; Asbestos; Cyclic AMP; Cyclic GMP; Male; Mesothelioma; Neoplasms, Experimental; Peritoneal Neoplasms; Rats