natriuretic-peptide--c-type and Skin-Neoplasms

In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer.

Topics: Bone and Bones; Cartilage; Cell Communication; Cell Proliferation; Chondrocytes; Fibroblast Growth Factors; Gene Expression Regulation; Genes, Lethal; Humans; MAP Kinase Signaling System; Mutation; Natriuretic Peptide, C-Type; Osteochondrodysplasias; Phosphatidylinositol 3-Kinases; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Skin; Skin Neoplasms; STAT1 Transcription Factor

C-type natriuretic peptide (CNP) exhibits anti-inflammatory activity besides its natriuretic and diuretic functions. The present study aimed to determine the anticancer and synergistic therapeutic activity of CNP against a 7,12-Dimethylbenz[a]anthracene (DMBA)/Croton oil-induced skin tumor mouse model. CNP (2.5 µg/kg body weight) was injected either alone and/or in combination with Cisplatin (CDDP) (2 mg/kg body weight) for 4 weeks. The dorsal skin tumor incidences/growth and mortality rate were recorded during the experimental period of 16 weeks. The serum C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels, infiltrating mast cells, and AgNORs proliferating cells count were analyzed in control and experimental mice. Further, the expression profile of marker genes of proliferation, inflammation, and progression molecules were analyzed using Reverse transcriptase-polymerase chain reaction (RT-PCR)/quantitative PCR (qPCR), western blot, and immunohistochemistry. The DMBA/Croton oil-induced mice exhibited 100% tumor incidence. Whereas, CNP alone, CDDP alone, and CNP+CDDP combination-treated mice exhibited 58%, 46%, and 24% tumor incidence, respectively. Also, a marked reduction in the levels of serum CRP and LDH, the number of infiltrating mast cells count and AgNORs proliferating cells count were noticed in the mice skin sections. Further, a significant reduction in both mRNA and protein expression levels of proliferation, inflammation, and progression markers were noticed in CNP (p < 0.01), CDDP (p < 0.01), and CNP+CDDP combination (p < 0.001) treated mice, respectively. The results of the present study suggest that CNP has anticancer activity. Further, the CNP+CDDP treatment has more promising anticancer activity as compared with CNP or CDDP alone treatment, probably due to the synergistic antiproliferative and anti-inflammatory activities of CNP and CDDP.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Anti-Inflammatory Agents; Body Weight; Croton; Croton Oil; Inflammation; Mice; Natriuretic Peptide, C-Type; Skin Neoplasms