Small cell lung cancer: Cause of treatment resistance discovered

A team of researchers has discovered a biological explanation for why patients with small cell lung cancer experience relapse some 12 months after successful treatment. They found that chemotherapy-resistant complexes develop from circulating tumor cells that were previously sensitive to treatment.

The researchers, from the Medical University of Vienna in Austria, report their findings in the journal Scientific Reports.

In the United States, lung cancer accounts for around 14 percent of all new cancers. Not counting skin cancer, the disease is the second most common cancer in both sexes: in men, it is second to prostate cancer, and in women, it is second to breast cancer.

Every year in the U.S., more people die of lung cancer than from colon, breast, and prostate cancers combined.

National estimates suggest that in 2017, approximately 222,500 people will be diagnosed with lung cancer and 155,870 will die of the disease.

There are three main types of lung cancer: non-small cell lung cancer, small cell lung cancer, and lung carcinoid tumor.

Aggressive cancer that spreads quickly

Small cell lung cancer (SCLC), which is the subject of the new study, is a type of cancer that usually spreads quickly and accounts for around 10 to 15 percent of all lung cancers.

The researchers note that the "great majority" of patients diagnosed with SCLC "consist of smokers with heavy tobacco consumption for decades."

They explain that in most cases, when patients first present with SCLC, the tumors are aggressive and have already spread, meaning that surgery is no longer an option.

Unfortunately, after a year of successful response to treatment with chemotherapy and radiotherapy, people with advanced SCLC usually relapse with tumors that resist further chemotherapy.

After this, the prognosis is very poor, and patients rarely live more than a few months.

Highly resistant 'tumorspheres'

Previously, while it was clear that the relapse was due to tumors that develop resistance to chemotherapy, there was no clear biological explanation.

Now, the new study shows that the mechanism of chemotherapy-resistance is that circulating tumor cells form highly resistant complexes.

"The circulating tumor cells aggregate to protect themselves from chemotherapy - like a circle of covered wagons - thereby preventing any active agents from entering," explains Dr. Gerhard Hamilton, of the Department of Surgery at the Medical University of Vienna.

The multicellular aggregates - which Dr. Hamilton and colleagues refer to as "tumorspheres" - comprise "hundreds of thousands of cells" and can measure up to 2 millimeters in diameter.

The tumorspheres can be eight times more resistant to chemotherapy drugs than the tumors were the first time around.

'Unique tumor model'

The researchers suggest three reasons for the increased chemotherapy-resistance in the tumorspheres.

First, because of the nature of the complex, many of the tumor cells are less accessible. Secondly, there is insufficient oxygen in the aggregate - that is, the conditions are "hypoxic."

The third reason that the authors give for increased chemotherapy-resistance in the tumorspheres is that they have a much smaller percentage of cells in the growth phase of the cell cycle, or a smaller "growth fraction."

The researchers point out that the study was made possible because they were able to develop seven different circulating tumor cell lines to produce the large numbers of cells needed. This had never been done before. The cell lines were derived from blood samples taken from patients with advanced SCLC in Vienna.

The authors note that similar tumorspheres have been found in other types of tumor.

"Universal chemo-resistance due to formation of large clusters may not be limited to SCLC but occur in other related tumors, such as glioblastoma and neuroectodermal tumors, as well."

They suggest that "SCLC seems to represent a unique tumor model" for studying the relationship between circulating tumor cells, metastasis, and drug resistance.