Lung Basal Stem Cells May Be the Originator of Squamous Cell Carcinoma

Lung basal stem cells (BSCs) rapidly repair DNA damage using the error-prone nonhomologous end-joining pathway, and ultimately pave the way for smoking-related lung cancer, a recent study indicates.

Squamous cell carcinoma (SqCC) is the second most common histological subtype of cancer that shows strong genomic instability. SqCC is almost exclusively found in smokers, with 96% of patients having a history of tobacco, according to the study.

The carcinogens found in cigarette smoke are most likely accountable for the significantly high mutational rate that is seen in SqCC compared with other cancers, the authors said.

In a study published in PLOS Biology, investigators isolated basal cells and alveolar progenitor cells from the lungs of patients who were heavy smokers, and compared their gene activity, the rates of cell division, and their ability to repair their DNA in response to damage.

The results of the study showed that only BSCs and alveolar type 2 (AT2) cells generated phenotypically distinct colonies. The BSCs formed clonal, hollow, spherical colonies, while AT2 colonies were saccular and less uniform, according to the authors.

Carcinoma cells from smokers carried the “transcriptional fingerprint” of BSCs, which suggests that the tumors may originate from this specific type of cell. Additionally, the investigators found that basal cells had superior efficacy in repairing damaged DNA, which allowed them to survive and reproduce after being exposed to chemicals or radiation that caused damage to the DNA.

The principal repair nonhomologous end joining pathway used by BSCs introduced numerous errors in the DNA. This rapid and error-prone repair may be the cause of why basal cells accumulate a high burden of mutations that results in carcinoma, according to the authors.

“Our results indicate that targeting DNA repair processes may be a promising approach to preventing and treating this form of lung cancer,” said author Marie-Liesse Asselin-Labat.

The study authors concluded that “heavy smoking promotes proliferation of BSCs, and their predilection for error-prone nonhomologous end joining could to the high mutagenic burden that culminates in lung squamous cell carcinoma. Targeting DNA repair processes may therefore have a role in the prevention and therapy of SqCC.”