Researchers identify ‘cheating’ cancer cell populations

According to studies from UConn Health, Yale, and Johns Hopkins, certain cancer cells are able to “cheat” by avoiding the limits brought on by an oxygen shortage. The cancer cells might continue to multiply as a result. Scientists Chi V. Dang from Johns Hopkins and Andre Levchenko from Yale, as well as Kshitiz, an assistant professor in the department of biomedical engineering, recently published their findings in the journal Cell Systems. When examining cancer cells in hypoxia—the lack of oxygen—nearly 10 years ago, researchers found an odd phenomena.

“As tumours grow and become large, they run out of oxygen and new blood vessels are created,” says Kshitiz. “This results in scarcity of oxygen, called hypoxia. Under hypoxia, cells are supposed to slow down their growth, but of course, cancers continue to grow larger. This presents a conundrum, yet unsolved.”

The scientists came to the conclusion that a tiny percentage of cells were “cheating,” or rewiring their signalling, in order to divide and expand. The researchers’ emphasis quickly shifted to figuring out how the cells were deceiving them and how this phenomena related to cancer diagnosis.

A protein termed HIF-1, a master regulator of the cells’ oxygen response, is stabilised by cells in hypoxic conditions. When the level of oxygen drops, HIF-1 signalling increases and causes the cells to stop functioning. HIF-1 causes cells to release proteins that draw blood arteries toward themselves, instructs the cell division machinery to cease functioning, and jump-starts anaerobic respiration utilising a significant amount of glucose.

In the study, the researchers found that a tiny proportion of cells oscillated HIF-1 rather than stabilising it, causing it to move up and down. Cells might avoid the HIF-1-imposed halt while HIF-1 oscillated and moved from up to down to up again. These oscillating cells pulled a fast one and kept on dividing in spite of the extremely low oxygen levels.

“To find cheaters within a population of cancer cells, which are themselves cheating the normal cells, is interesting at so many levels,” Kshitiz says.
“We have observed oscillations in many systems, but oscillations in HIF-1 activity were not recorded before, and it is truly remarkable,” Levchenko adds. “We are particularly interested in how oscillations like these can be recognized as a signal triggering specific genes.”

Researchers also discovered that cancer cells interact with one another, enabling cells to gauge the density of other cells. Because of hypoxia, cells may create energy without oxygen when HIF-1 levels are high. As a consequence, lactate is produced, which is the same chemical that causes cramps when we exercise when the muscles are not receiving enough oxygen. Lactate builds up in the surroundings of cancers.

At the University of California, San Francisco, Kshitiz collaborated with professor Junaid Afzal to determine the precise method through which lactate destabilised HIF-1.

“Excess lactate forces cells to undergo respiration, even when oxygen is scarce, and that caused degradation of HIF-1 in lysosomes, the recycling centres in a cell,” says Afzal.

Do these discoveries made under a microscope have any relevance to actual cancer cases, though? The best technique to test these hypotheses in animal subjects, let alone humans, is not available with current technology.

Using this newly discovered knowledge, Kshitiz and Yasir Suhail, a postdoctoral researcher in Kshitiz’s group at UConn Health, examined the genetic composition of several tumours that affect people.

“What we found was truly astounding,” says Kshitiz. “Most genes behaved as expected, but there was a group of genes which behaved opposite to what is expected in hypoxia. It did not make much sense; why should genes which turn on in hypoxia, turn off when hypoxia is oscillating? Clearly, something is at play.”

Suhail examined these genes in all human tumours in an effort to gain a better understanding and discovered a common occurrence. Most malignancies had the genes that oscillations switched off, indicating that decreasing tumour suppressor genes and promoting cancer growth may be caused by oscillations in HIF-1 levels.
Kshitiz asserts: “The fact that the phenomena occurs in every malignancy is the most intriguing feature. It appears that this impact affects all cancers, not just one specific type.”

Kshitiz says, “The most interesting aspect is the universality of the phenomenon in all cancers. It seems this effect is pan-cancer, and not just in any cancer.”

The discovery, which unravels this extraordinary phenomena, provides new avenues for scientific investigation while providing solutions to various cancer-related mysteries.

“It is a large collaboration across many institutions, a testament to how deep scientific questions require the integration of many types of expertise to come together,” says Kshitiz.