Small cell lung cancer: the world of highly lethal cancers

Small cell lung cancer: the world of highly lethal cancers
© iStock/Natali_Mis

Researchers from Weill Cornell Medicine studied highly lethal cancers, using human embryonic stem cells to create a new model system specifically exploring small cell lung cancer.

Published in Journal of Experimental Medicine (JEM), by studying the initiation and progression of small cell lung cancer (SCLC), research reveals the distinct roles played by two critical tumour suppressor genes that are commonly mutated in these highly lethal cancers.

The aggressively lethal cancer that is small cell lung cancer

Small cell lung cancer is found almost exclusively in smokers and usually becomes resistant within several months to existing treatments, such as chemotherapy and radiotherapy.

Over the past 30 years, little development has been made in progressing new treatments for the disease, causing the US Congress and National Cancer Institute to designate it as a ‘recalcitrant’ cancer.

One reason for the lack of new treatments is the rapid onset and progression of small cell lung cancer, making it difficult to obtain clinical samples for researchers to study.

In recent few years, models for studying SCLC have been developed in mice. The authors of the new report in JEM describe an alternative way to study tis highly lethal cancer in human cells by growing embryonic stem cells in culture and differentiating them into various types of lung cells capable of becoming cancerous.

Developing highly lethal cancers

Small cell lung cancer is thought to develop from a particular type of lung cell, called pulmonary neuroendocrine cells (PNECs), but until now, no one knew how to induce human embryonic stem cells to become PNECs in the lab.

Huanhuan Joyce Chen, one of the lead authors on the study explains: “We discovered a means to induce pulmonary neuroendocrine-like cells from cultured human embryonic stem cells after first differentiating them into lung progenitor cells.”

“We did this by blocking an important cell signalling pathway known as the NOTCH pathway.”

Almost all patients with SCLC carry mutations that inactivate two key tumour suppressor genes called RB and TP53.

The researchers found that lung progenitors formed even more PNECs when their RB gene was inhibited in addition to the NOTCH signalling pathway. Moreover, RB-deficient PNECs expressed a set of genes very similar to those expressed by early-stage SCLC tumours, although they were unable to form tumours when injected into laboratory mice.

However, when Chen and colleagues also inhibited the TP53 gene, the PNECs began to express genes that promote cell proliferation and prevent cell death, and cultures containing these PNECs formed slowly growing tumours when injected under the skin of mice.

The results suggest that mutations in the RB and TP53 affect two aspects of initiation of small cell lung cancer.

“Our system should enable further studies of the progression of these early-stage tumours into invasive SCLCs that resemble the more aggressive cancers found in patients,” says Harold Varmus, co-lead author of the study and Lewis Thomas University Professor at Weill Cornell Medicine, USA.

“If so, it should be possible to test cells at different stages of tumour development for susceptibility and resistance to therapeutic strategies.”


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