Scientists discover a surprising danger in smaller cancer cells

The discoveries emerged from years of painstaking laboratory work, including the careful examination of tumors grown in mice.

Graduate student Megan Sweet, who studies biological sciences at Virginia Tech, spends much of her time preparing extremely thin slices of tumor tissue. Working inside a refrigerated metal chamber, she carefully adjusts a mounted tumor, roughly the size of a pinkie fingernail, toward a sharp cutting blade.

"It's all about fine-tuning and making sure it's going to be an even slice," said Sweet, who studies biological sciences.

As the blade moves through the tissue, it produces a steady, rhythmic chopping sound.

"This is the hardest and most time-consuming part," Sweet said. "But it's also kind of meditative."

Each section is cut so thin that light can pass through it. Sweet carefully transfers the delicate tissue onto a glass slide, where selected cellular structures are stained to make them easier to distinguish under a powerful microscope.

The process involves repeated rounds of cutting, staining, examining, and comparing samples. Although painstaking, this work is helping scientists piece together why certain tumors become much more dangerous than others.

The Virginia Tech team has published findings that shed new light on how cancer develops and progresses. Their research was published in the Proceedings of the National Academy of Sciences, with additional findings published earlier this year in Cancer Research.

How Chromosome Errors Can Fuel Cancer

Most healthy cells in the human body are diploid, meaning they contain two complete sets of chromosomes, with one inherited from each parent.

Under normal conditions, these cells divide to produce new cells with the same chromosome arrangement. Occasionally, however, something goes wrong during division, leaving cells with an abnormal number of chromosomes.

When these errors are passed on during subsequent cell divisions, they can accumulate over time. Such changes are one of the ways cancer can develop.

For the past five years, Sweet and fellow graduate student Mat Bloomfield have worked with cell biologist Daniela Cimini to investigate cells carrying abnormal numbers of chromosomes, a common characteristic of cancer.

To study the consequences of these abnormalities, Cimini's team manipulated diploid cancer cells so they would duplicate their chromosomes without completing cell division.

The result was a type of cell known as a tetraploid cell, which contains four complete sets of chromosomes rather than the usual two.

These cells are not limited to laboratory experiments. Tetraploid cells can also emerge during the development of human tumors, and their presence has been associated with cancer progression and poorer outcomes for patients.

Cancer Cells Recruit Healthy Cells to Fuel Tumor Growth

Scientists have long recognized that tetraploid cells can make tumors more aggressive. What remained unclear was exactly how they contributed to cancer growth.

To investigate, Sweet and Bloomfield compared tumors that developed from ordinary diploid cancer cells with those formed from tetraploid cancer cells.

The experiments produced an unexpected result.

As tumors grew in mice, the proportion of tetraploid cells actually decreased. Despite this decline, the tumors continued expanding rapidly and reached substantial sizes.

The researchers discovered that tetraploid cancer cells were encouraging the recruitment of stromal cells, which are noncancerous connective tissue cells that help provide structural support.

These additional cells appeared to create an environment that favored further tumor development.

"The presence of even a small fraction of these tetraploid cells can promote the recruitment of extra non-cancerous cells that support further tumor progression," Sweet said.

The finding revealed a previously unrecognized mechanism through which abnormal cancer cells can promote tumor growth, even when they account for only a small portion of the tumor.

Smaller Cancer Cells Reveal a Surprising Danger

A separate investigation uncovered another unexpected connection between tetraploid cells and cancer aggressiveness.

Bloomfield was initially examining the physical characteristics of tetraploid cells. After producing tetraploid cells from human cancer cells and establishing colonies derived from individual cells, he noticed that the resulting groups were not all the same size.

Because tetraploid cells contain twice the usual number of chromosome sets, the researchers expected them to be approximately twice as large as diploid cells.

Instead, some of the cells were 25 to 30 percent smaller than anticipated.

Even more surprisingly, those smaller cells proved to be more capable of forming aggressive tumors than their larger counterparts.

"The smaller clones are more aggressive," Bloomfield said. "They grow faster, are more invasive, and more tolerant of common anti-cancer and stress-inducing drugs."

Further experiments in mice supported these observations. Tumors containing smaller tetraploid cells frequently grew more quickly than those containing larger ones.

The pattern was not restricted to a single type of cancer. Researchers observed similar results in both colorectal and breast cancer cells, suggesting that the relationship between tetraploid cell size and tumor aggressiveness may extend across different cancers.

Cancer Cell Size May Help Predict Patient Survival

The researchers next examined whether the same relationship could be found in human cancers.

They analyzed information from the Cancer Genome Atlas, a large collection of detailed data from thousands of cancer patient samples.

The results revealed that smaller tetraploid cells were associated with worse prognoses and lower survival rates across several cancer types.

This suggests that measuring the size of these abnormal cells could provide valuable information about how aggressively a tumor might behave.

"We already knew that tetraploidy can make cells more tumorigenic, but now we know that if you incorporate the size of the cells, it can be more predictive of tumorigenic potential," Cimini said.

The findings add an important dimension to scientists' understanding of cancer. Abnormal chromosome numbers have long been linked to dangerous tumor behavior, but the new research indicates that cell size may offer additional clues about a cancer's potential to grow and spread.

The team now plans to investigate the biological mechanisms responsible for these effects in greater detail while continuing to examine human cancer data.

For Sweet, that means more hours at the laboratory bench, carefully cutting and analyzing tiny sections of tumor tissue in the search for answers to one of cancer biology's most important questions.