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TRACKING THE IMPACT OF WATERPIPE SMOKE ON LUNG CANCER MALIGNANCY
As waterpipe smoking gains popularity worldwide, one research project delves into how the seemingly harmless pastime amplifies the danger of lung cancer and demonstrates its effect in live cells.
Waterpipe smoking, or shisha as it is known in the UAE, is a pastime and social activity that many perceive as harmless. However, evidence is mounting that it can increase one’s risk of cancer by reducing the body’s ability to recognize and kill cancer cells, while enhancing their ability to evade treatment and spread in the body.
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To that end, a project led by Dr. Rania Faouzi Zaarour, Assistant Professor and Researcher at the Thumbay Research Institute for Precision Medicine (TRIPM) at Gulf Medical University (GMU), has investigated how waterpipe smoke condensate (WPSC) exposure increases the danger posed by cancer on the body by reducing immune response and increasing cancer-cell resilience.
“We became interested in waterpipe smoking because of its increasing popularity around the world, particularly among the youth,” she shared. “This is despite the fact that waterpipe smokers are actually exposed to even more toxic molecules than cigarette smokers, as a waterpipe smoking session typically lasts far longer than a cigarette. Given the growing numbers of waterpipe users and the lack of research into the unique effects of WPSC on lung cancer cells, we felt this was an important topic to explore.”
The World Health Organization reports that the Eastern Mediterranean Region, in which the UAE falls, has the highest prevalence of waterpipe use in the world – particularly among young people. It lists waterpipe smoke as toxic, with links to both lung and oral cancer alongside other adverse health outcomes. Dr. Zaarour and her collaborators from GMU, American University of Sharjah (AUS), and the Gustave Roussy Cancer Campus in France focused their research on three major cell functions.
The first, cell proliferation, refers to the process by which cells grow and divide to produce more cells. Cancer cells tend to proliferate faster than healthy cells, spreading rapidly in the body. The second function, cell plasticity, is the ability of some cells (like stem cells) to switch from one specific program of gene expression to another in response to specific signals from the environment. Some cancer cells demonstrate stem cell-like plasticity, shifting between different states and evading immunotherapy and the immune system in the process. The third is tumor recognition and removal, a function of natural killer (NK) cells that are part of the immune system. NK cells become activated in the presence of foreign cells like tumors or viruses, which they target for removal by releasing cell-destroying toxins.
“NK cell-mediated immune surveillance strengthens host defense against certain microbial agents and cells undergoing malignant transformation,” explained Dr. Zaarour. “To date, no data is available as to the effect of waterpipe smoke on NK cell function, although in mice, waterpipe smoke condensate exposure has been found to suppress immunity, while cigarette smoking has been linked to lower populations and activity of NK cells.”
Left to right: Dr Goutham Hassan Venkatesh, Ms. Ayesha Rifath, Mr. Husam Hussein Nawafleh, Dr. Rania Faouzi Zaarour, Ms. Nagwa Ahmed Zeinelabdin, Dr. Raefa Abou Khouzam
To understand how waterpipe smoking affects lung cells and lung cancer cells, researchers grew different types of cells in the lab, including two lines of cancerous lung cells (H460 and A549) and one line of non-cancerous lung cells – all from human samples. The cells were then exposed to WPSC of double appleflavored waterpipe tobacco through a machine that mimics the way humans inhale and puff. The cells were tested in the presence of various concentrations of WPSC condensate (0.5%, 1%, and 2%) for eight consecutive days. NK cells were then added to the three types of lung cells to see how the WPSC exposure impacted their activity.
- Dr. Rania Faouzi Zaarour, Assistant Professor and Researcher at the Thumbay Research Institute for Precision Medicine
The two cancerous cell line samples were analyzed to see how WPSC impacted altered gene expression related to DNA damage, inflammation, epithelial to mesenchymal transition (EMT), and stem cell-like qualities in the lungs. EMT is a biological process that allows an epithelial cell (the type of cell on the surface of the skin, blood vessels, urinary tracts, or organs that protects it from viruses) to become a type of cell that can travel, invade, and produce other cell matrices. In the context of cancer, EMT enables the cancerous cells to travel and spread throughout the body.
The researchers found that exposure to WPSC induced DNA damage, which is a precursor to cancer. WPSC exposure was also found to result in decreased cell proliferation, with cell death at higher concentrations proving a positive correlation. In the lung cancer cell line, WPSC was found to activate the inflammatory response that is believed to contribute towards tumor formation. Expression of EMT and production of cancer stem cells were also found to be increased by WPSC exposure, which in turn can increase the aggressiveness of a tumor. The effect of WPSC exposure on the ability of NK cells to recognize and kill cancer cells was also studied and found to be significantly reduced in one cancer cell line, but not the other.
Explaining the results, Dr. Zaarour said: “We observed that pathways involved in the induction of EMT, a prerequisite for cancer stem cell generation, were turned on. We also observed an increase in DNA damage and inflammation induced by waterpipe smoke exposure. Inflammation plays an important role in the tumorspecific microenvironment, which is thought to facilitate all phases of tumor production, from initiation to spreading to other parts of the body. Lastly, we investigated how these WPSC lung cancer cells’ susceptibility to NK cells was impacted by exposure to WPSC, and found that they became more resistant to killing, although they did not become harder to recognize by the NK cells.”
Regarding the different impacts of WPSC on the cancer-killing ability of the two cancer cell lines, she continued: “Under our experimental conditions, WPSC exposure reduced the cell-killing activity of one of the cancer cell lines, A549, but not in the other. However, the capacity of the NK cells to form synapses with the WPSC-treated cancer cells was unaffected in both. This is most likely due to genetic variations in the two cell lines, engaging communication networks that could also include the release of inflammatory mediators signaling to the immune system. The finding raises further questions about different ways that WPSC can impact a cell’s susceptibility to lysis, which is the disintegration of a cell by the rupture of its wall.”
The research project also provides concrete evidence of how waterpipe smoking impacts the pathology of lung cancer, according to Dr. Zaarour. “Our study shows that continuing smoking waterpipe after being diagnosed with lung cancer may result in more aggressive behavior by cancer cells. This means therapy modalities for cancer patients would be more effective if they eliminated waterpipe smoking entirely. Additionally, targeting inflammatory mechanisms may help control the emergence of aggressive cancer clones with EMT and stem cell-like features,” she said.
A paper on the collaborative research project was recently published in the reputed Oncology Reports journal. Dr Zaarour’s co-authors from TRIPM at GMU included Dr. Prathibha Prasad, Lecturer and Researcher; Dr. Goutham Hassan Venkatesh, Assistant Professor and Researcher; Dr. Raefa Abou Khouzam, Assistant Professor and Researcher; Dr. Francis Amirtharaj, Assistant Professor and Researcher; Nagwa Zeinelabdin, Research Assistant; Ayesha Rifath, Research Assistant; Husam Nawafleh, Cellular Imaging in Charge; and Dr. Salem Chouaib, Institute Director. Other collaborators included Stéphane Terry, Research Scientist at Gustave Roussy, ParisSud University, Paris-Saclay University, and Dr. Yehya El-Sayed, Professor at AUS.
As a next step, Dr. Zaarour and her collaborators will investigate the specific pathways leading to lung cancer’s stem cell generation in response to WPSC exposure, as well as how WPSC-mediated cell mutation prompts specific molecular pathways. “These, in turn, could promote tumor growth by inhibiting immune system recognition and killing, which will help unveil clues to enhance cancer treatment modalities,” she concluded.
