Nav: Home

Smoking slowly changes lung cells to increase the odds for cancer

September 11, 2017

Cigarette smoke causes epigenetic changes in lung cells that prime them to develop cancer, and researchers can now observe how these changes unfold over time. Reporting September 11 in the journal Cancer Cell, Johns Hopkins University School of Medicine investigators show that healthy lung cells in a dish exposed to cigarette smoke condensate for 10-15 months--the equivalent of someone smoking 20-30 years--have accumulated epigenetic abnormalities associated with abnormal "turning off" of multiple genes, which are otherwise needed to help protect normal cells from developing cancer.

These changes are accompanied by increased activity of cell signals that would indicate the presence of a mutation in a key oncogene, KRAS; yet no such mutation was present in this or other genes frequently mutated in lung cancer. However, if the investigators inserted a KRAS mutation into the cells with the epigenetic abnormalities, they became cancerous with just this one step and having this one mutation. Introduction of mutant KRAS into healthy cells without chronic exposure to cigarette smoke condensate was not enough to induce tumors.

Studies in The Cancer Genome Atlas and other databases have shown that about 30 % of lung adenocarcinomas, the most frequent type of lung cancer, have KRAS mutations. These tumors also frequently harbor the epigenetic abnormalities produced by the cigarette smoke condensate exposure used in the above lab studies.

"When you're smoking, you are building up a substrate of epigenetic changes that we hypothesize are increasing your mathematics for developing lung cancer, because if you're not a smoker, your risk of lung cancer is very low," says senior author Stephen B. Baylin, co-director of the Cancer Biology program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Hopkins scientist, co-corresponding author Hari Easwaran. "If you are a smoker, however, while you still have 8 or 9 out of 10 chances not to get lung cancer, the mathematics are now still very robustly much more going against you, and maybe it's because there are these epigenetic changes that build up."

Baylin and his colleagues show that lung cells--engineered for these experiments to survive in a laboratory dish in the presence of cigarette smoke condensate--begin to behave abnormally within 10 days of smoke exposure. The first changes are cellular signs of DNA damage and tighter binding to DNA of proteins that help establish the above epigenetic changes. However, only after 10 to 15 months, but not earlier, the DNA is covered in a dramatic number of abnormal methylation marks at the start sites of multiple genes, which is associated with the silencing of the protective genes discussed earlier. DNA methylation is an example of an epigenetic change, as it modifies gene expression rather than altering the basic DNA sequence of the gene.

The researchers identified that the epigenetic changes in the chronically exposed lung cells are responding to smoking by regressing into a more stem-cell like state, meaning that they are priming themselves to self-renew. Mature cells normally repress the types of cell signaling pathways in which KRAS is a key player to help prevent uncontrolled growth. Multiple genes that are silenced with the abnormal epigenetic changes induced by the cigarette smoke exposure would normally act to turn down KRAS signaling.

To test their theory for the role of the epigenetic abnormalities observed, Baylin and his team introduced a single KRAS mutation in lung cells, both exposed and not exposed to cigarette smoke extract, and then transplanted them into mice. The cells exposed for only 6 months did not become cancerous, but, indeed, those exposed for 15 months, which harbored the epigenetic abnormalities, did become cancerous and form lung adenocarcinomas in the mice.

"This work suggests the possibility that unlike mutations, which are harder to reverse, if you stop smoking at a certain time and duration, then you have a chance to decrease your likelihood of getting cancer that might be due to the buildup of epigenetic changes," says first author Michelle Vaz, a postdoctoral researcher at Johns Hopkins University School of Medicine. "The hypothesis is that there are potentially reversible changes that are contributing to a certain set of lung cancers."

Baylin, Easwarn, Vaz, and their collaborators are now exploring the possibility of using therapies that target the specific epigenetic changes that occur in the lung cells of smokers.


The research was supported by the National Cancer Institute, the National Institutes of Health, and the National Institute of Environmental Health Sciences.

Cancer Cell, Vaz et al: "Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single Step Transformation by KRAS Mutations."

Cancer Cell (@Cancer_Cell), published by Cell Press, is a monthly journal that provides a high-profile forum to promote major advances in cancer research and oncology. The journal covers topics related to molecular and cellular mechanisms of cancer, mechanisms for the sensitivity and the resistance to cancer therapies, development of better cancer therapies, and clinical investigations. Visit: To receive Cell Press media alerts, contact

Cell Press

Related Lung Cancer Articles:

AI helps to fight against lung cancer
Lung cancer has been the leading cause of cancer-related deaths in 2015 in United States.
Free lung-cancer screening in the Augusta area finds more than double the cancer rate of previous screenings
The first year of free lung cancer screening in the Augusta, Ga., area found more than double the rate seen in a previous large, national study as well as a Massachusetts-based screening for this No.
Antioxidants and lung cancer risk
An epidemiological study published in Frontiers in Oncology suggests that a diet high in carotenoids and vitamin C may protect against lung cancer.
Lung cancer may go undetected in kidney cancer patients
Could lung cancer be hiding in kidney cancer patients? Researchers with the Harold C.
Hitgen and Cancer Research UK's Manchester Institute enter license agreement in lung cancer
Cancer Research UK, Cancer Research Technology (CRT), the charity's commercial arm, and HitGen Ltd, a privately held biotech company focused on early drug discovery, announced today that they have entered into a licence agreement to develop a novel class of drugs against lung cancer.
Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Huntsman Cancer Institute research holds promise for personalized lung cancer treatments
New research from scientists at Huntsman Cancer Institute (HCI) at the University of Utah uncovered distinct types of tumors within small cell lung cancer that look and act differently from one another.
High levels of estrogen in lung tissue related to lung cancer in postmenopausal women
Researchers from Kumamoto University, Japan have found that postmenopausal women with multicentric adenocarcinoma of the lung have a higher concentration of estrogen in non-cancerous areas of the peripheral lung than similar women diagnosed with single tumor lung cancer.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Pericardial window operation less efficient in cases of lung cancer than any other cancer
Pericardial window operation, a procedure, where abnormal quantity of malignant fluid, surrounding the heart, is drained into the neighbouring chest cavity, is commonly applied to patients diagnosed with cancer.

Best Science Podcasts 2017

We have hand picked the best science podcasts for 2017. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: Radiolab

Radiolab Presents: Anna in Somalia
This week, we are presenting a story from NPR foreign correspondent Gregory Warner and his new globe-trotting podcast Rough Translation. Mohammed was having the best six months of his life - working a job he loved, making mixtapes for his sweetheart - when the communist Somali regime perp-walked him out of his own home, and sentenced him to a lifetime of solitary confinement.  With only concrete walls and cockroaches to keep him company, Mohammed felt miserable, alone, despondent.  But then one day, eight months into his sentence, he heard a whisper, a whisper that would open up a portal to - of all places and times - 19th century Russia, and that would teach him how to live and love again. 
Now Playing: TED Radio Hour

Future Consequences
From data collection to gene editing to AI, what we once considered science fiction is now becoming reality. This hour, TED speakers explore the future consequences of our present actions. Guests include designer Anab Jain, futurist Juan Enriquez, biologist Paul Knoepfler, and neuroscientist and philosopher Sam Harris.