Chronic exposure to cigarette smoke makes cells that maintain and repair the lungs more vulnerable to cancer-causing gene alterations, according to new research.
Using mini-lungs grown from lung stem cells in the laboratory, researchers observed changes in lung cells over six months of exposure to chemicals and particles contained in cigarette smoke.
The chronic exposure altered gene programming and gene activity in the lung cells, creating distinct precancerous states, according to a report published in PNAS.
Among the notable changes was suppression of inflammatory and immune signaling pathways and genes involved in programmed cell death.
When researchers introduced two gene variants commonly associated with smoking-related lung cancer, KRAS and TP53, the altered stem cell populations responded differently.
KRAS mutations drove lung adenocarcinomas primarily from cells derived from so-called bronchioalveolar stem cells, while loss of the tumor suppressor gene TP53 produced squamous cell carcinomas derived from basal stem cells.
Researchers have long known that mutations in genes such as KRAS and TP53 can drive lung cancer. But the mutations are also seen in normal or precancerous tissue, suggesting that on their own, they may not be sufficient to start cancer.
To test whether cigarette smoke exposure made the cells more susceptible to transformation by cancer-driving mutations, the researchers implanted smoke-exposed mini-lungs and unexposed mini-lungs in mice.
Only the smoke-exposed organoids containing one of the genetic alterations formed tumors. Cigarette smoke exposure alone did not produce tumors, nor did introducing the genetic alterations into organoids not exposed to smoke.
The findings help explain how environmental exposure, chemical changes and genetic mutations may work together during the earliest stages of non-small cell lung cancer, the most common type of lung cancer, the researchers said.
Study leader Michelle Vaz of Johns Hopkins University expressed excitement about the prospects of using this knowledge, in combination with other therapies, to come up with drugs that "help tumors that currently do not respond to treatment, respond better.”
