Nicotine promotes growth of tumors already established by tobacco carcinogens
While it is established that nicotine by itself is not carcinogenic, researchers have now shown that nicotine promotes cell proliferation and the progression of tumors already initiated by tobacco carcinogens. In a study by Srikumar Chellappan and colleagues from the University of South Florida appearing online on July 20 in advance of print publication in the August issue of the Journal of Clinical Investigation, the authors show that the presence of receptors that bind nicotine, known as nicotinic acetylcholine receptors (nAChRs), on bronchial cells as well as lung cancer cells are key to nicotine-induced cell proliferation of lung cancer cells.
nAChRs function mainly in the neuronal system, however recent studies have shown their expression and function in non-neuronal systems as well. In the current study, the authors show that stimulation of human non–small cell lung cancers (NSCLCs) as well as cells lining the air passages of the lung (known as bronchial cells) with a physiological concentration of nicotine leads to robust cell proliferation that is dependent on nAChRs.
Furthermore, nicotine appears to activate the major components of the cell proliferation cycle in a manner very reminiscent of growth factors. Specifically, nicotine stimulation leads to the binding of Raf-1 to Rb, activation of cyclin-dependent kinases, phosphorylation of Rb, and recruitment of E2F1 to proliferative promoters.
Previous studies had shown that interfering with the interaction of Rb and Raf-1 prevented cell growth and tumor growth. In the current study the same appears to be true for nicotine stimulation of cells. A role for the Rb–Raf-1 interaction in the genesis of lung cancer is further supported by the observation that there was more Raf-1 associated with Rb in 8 out of 10 tumor samples examined, compared to the adjacent normal tissues. These observations suggest a role for Rb–Raf-1 interaction in the genesis of lung cancer.
These studies shed new light on the previously unknown mechanisms underlying nicotine-induced cell proliferation in lung cancer cells – namely that functional nAChRs on bronchial cells as well as lung carcinoma cells enable nicotine to promote the growth of established tumors.
TITLE: Nicotine induces cell proliferation by beta-arrestin–mediated activation of Src and Rb–Raf-1 pathways
University of South Florida, Tampa, Florida, USA.
Phone: (813) 745-6892; Fax: (813) 745-6748; E-mail: ChellaSP@moffitt.usf.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28164
Tackling tumor-associated macrophages beats breast and other cancers in mice
Tumor-associated macrophages (TAMs) can promote the growth and spread of tumor cells. In a study appearing online on July 20 in advance of print publication in the August issue of the Journal of Clinical Investigation, Rong Xiang and colleagues from The Scripps Research Institute have designed a cancer vaccine to specifically target these cells.
In this study, TAMs but not tumor cells or other macrophage populations, were found to express high levels of the enzyme legumain, so the authors generated a DNA vaccine encoding legumain. When administered to mice, this vaccine inhibited tumor growth and spread in mouse models of breast, colon, and non–small cell lung cancer. These effects appeared to result from legumain-specific CD8+ T cells targeting TAMs around the tumor for killing. Consistent with the marked decrease in the number of TAMs in the tumor tissue of vaccinated mice, tumors contained decreased amounts of the tumor cell growth factor TNF and the growth factor VEGF, which resulted in reduced tumor cell spread and limited the growth of new blood vessels to the tumor. The authors suggest that this demonstration that targeting TAMs can suppress tumor growth and metastasis could lead to the development of new therapies for cancer.
TITLE: Targeting tumor-associated macrophages as a novel strategy against breast cancer
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-8124; Fax: (858) 784-2708; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27648
Too old, too soon: potential treatment for progeria
Hutchinson-Gilford progeria syndrome (HGPS) is a rare pediatric syndrome causing physical changes that resemble greatly accelerated aging in sufferers. These symptoms include slow growth, wrinkled skin, hair loss, small face and jaw, pinched nose, osteoporosis, and atherosclerotic vascular disease. Currently, there are less than 50 known cases of HGPS in the world and most progeria patients die at around 13 years of age. HGPS is caused by a mutation in the Lamin A gene (LMNA) that results in the synthesis of a mutant prelamin A (also called progerin). Progerin undergoes farnesylation but cannot be further processed to mature lamin A, a key structural component of the cell nucleus. In HGPS cells, progerin accumulates at the rim of the nucleus, causing misshapen nuclei.
In a study appearing online on July 20 in advance of print publication in the August issue of the Journal of Clinical Investigation, Loren Fong and colleagues from the University of California, Los Angeles, suspected that protein farnesylation might be crucial for the aberrant targeting of progerin to the inner nuclear membrane and were able to show that blocking farnesylation with an inhibitor would prove therapeutic. Treatment of a new gene-targeted mouse model of HGPS with an inhibitor of farnesyltransferase (FTI) increased adipose tissue, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs may be useful for treating humans with HGPS.
TITLE: A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation
Loren G. Fong
University of California, Los Angeles, California, USA.
Phone: (310) 825-4934; Fax: (310) 206-0865; E-mail: email@example.com.
Stephen G. Young
University of California, Los Angeles, California, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28968
Pseudomonas needs neuraminidase for pulmonary infection
Therapeutics targeting a surface-bound enzyme encoded by the influenza virus neuraminidase are highly effective antiviral treatments. Although many bacterial pathogens, including the opportunistic pathogen Pseudomonas aeruginosa, also encode neuraminidases, whether these enzymes are important for bacterial pathogenesis such that they would be appropriate antibacterial targets has not been clear, until now.
In a study appearing online on July 20 in advance of print publication in the August issue of the Journal of Clinical Investigation, Alice Prince and colleagues from Columbia University report that mice rapidly clear bacteria from the respiratory tract following intranasal infection with mutant P. aeruginosa lacking neuraminidase whereas they cannot clear wild-type P. aeruginosa. In contrast, mice were equally susceptible to intraperitoneal infection with wild-type and mutant P. aeruginosa, indicating a role for neuraminidase in the initial stages of respiratory infection.
P. aeruginosa often grows in a biofilm – a complex clustering of microorganisms marked by the excretion of a protective and adhesive matrix material that helps organisms to adhere to surfaces and communicate with each other. In the current study the authors' analysis showed that biofilm formation by mutant P. aeruginosa lacking neuraminidase was markedly impaired and that biofilm formation by wild-type P. aeruginosa could be abrogated in a dose-dependent manner by influenza virus neuraminidase inhibitors. These data indicate that the P. aeruginosa neuraminidase is crucial for the initial colonization of the respiratory tract and have led the authors to suggest that neuraminidase could provide a new target to prevent infection with this bacterium. This would be a particularly welcome development for cystic fibrosis patients, who are predisposed to P. aeruginosa infection of the lungs.
TITLE: Bacterial neuraminidase facilitates mucosal infection by participating in biofilm production
Columbia University, New York, New York, USA.
Phone: (212) 305-4193; Fax: (212) 342-5728; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27920
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