Minor Clone May Drive Cancer Growth

The most dominant cell type within a tumor is not necessarily the most dangerous, new research suggests. Rather, a small population of cancer cells may be responsible for driving a cancer's growth and spread.

The findings offer new information about the many genetically distinct cells within a tumor, a phenomenon called intratumor heterogeneity (Nature 2014 July 30 [Epub ahead of print]).

“Heterogeneity is important,” says the study's senior author Kornelia Polyak, MD, PhD, a researcher at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, MA. “We need to figure out what is really making tumors grow and target those cells, not just the cells that seem to be the most common within tumors.”

Researchers have generally assumed that a tumor's growth was fueled by its largest subgroup of cells, the so-called dominant clone. This notion was based on what has been seen in lab-grown homogeneous cancer cell lines, not actual tumors, Polyak says.

To mimic what happens in actual tumors, researchers utilized a breast cancer cell line that created indolent tumors when xenografted into mice. From the same cell line, they generated a panel of 18 subpopulations, or subclones, by overexpressing in each subclone a different protein linked to cancer progression.

They then compared the phenotypic properties of tumors and clonal expansions in two experiments. In the first, mice were implanted with a single subclone that competed against its parental cells at a 1:18 ratio. In the second, mice were implanted with a mixture of the 18 different subclones. In both experiments, subclones that overexpressed the protein IL11 were able to drive tumor growth. In contrast, a subgroup that overexpressed the protein LOXL3 did not increase cancer growth despite taking over a large portion of the tumor.

“The minor subpopulation of IL11-expressing cells never grew to become a dominant clone, but it was still responsible for driving tumor outgrowth,” says Polyak, adding that IL11 appears to change the tumor microenvironment by recruiting stromal cells and promoting angiogenesis.

Researchers also observed that when all 18 subclones were present in the same tumor, they interfered with one another's expansion. “Clonal interference can limit tumor growth,” Polyak says. “Decreasing heterogeneity—which sometimes happens in treatment—is not always good because you might be favoring the growth of cancer cells with less favorable properties such as those resistant to treatment.”

The best treatment approach, she says, would be to develop drug combinations based on the heterogeneity of the tumor. Currently available drugs could be applied more effectively if scientists better understood their effects on the tumor, says Polyak.

“Further studies will hopefully help us identify and target the true drivers and potentially slow down the growth of the tumor, even if we cannot cure it,” she says.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.