Chromium (VI) promotes lung cancer initiation by activating EGF/ALDH1A1 signalling.

ABSTRACT

Lung cancer is the leading cause of cancer-related death worldwide and is strongly associated with tobacco smoke exposure. Though smoking remains the most important and best studied risk factor, recent data suggests that several other carcinogens have a driving role in lung cancer development, particularly in select populations at risk of high or prolonged exposure. Hexavalent chromium [Cr(VI)] is a known carcinogen that is widely used in the manufacturing industry. While the link between Cr(VI) and lung cancer incidence is well-accepted, the mechanisms through which Cr(VI) promotes lung cancer development are poorly understood. In the present study by Ge and colleagues published in Clinical and Translational Medicine, the authors explored the effects of prolonged Cr(VI) on non-malignant lung epithelial cells. They determined that Cr(VI) initiates lung tumorigenesis by transforming a subpopulation of stem-like, tumor initiating cells with increased expression of Aldehyde dehydrogenase 1 family member A1 (ALDH1A1). The observed increase in ALDH1A1 was dependent on transcriptional upregulation via Krüppel-like factor 4 (KLF4), and associated with enhanced Epidermal Growth Factor (EGF) biosynthesis. Cr(VI)-transformed tumor initiating cells accelerated tumor formation in vivo, which was ameliorated by therapeutic inhibition of ALDH1A1. Importantly, ALDH1A1 inhibition also sensitized Cr(VI)-driven tumors to Gemcitabine chemotherapy and extended overall survival in mice. This study not only offers novel insight into the mechanisms through which Cr(VI) exposure initiates lung tumorigenesis, but identifies a potential therapeutic target for patients with lung cancer secondary to Cr(VI) exposure. Additionally, this study underscores the importance of limiting exposure to Cr(VI) in the workplace and finding safer alternatives for use in the manufacturing industry.