Groups of people in cancer that "trick" cells

Researchers at the University of Connecticut Health Center, Yale University and Johns Hopkins University have found that some cancer cells can "trick" into allowing cancer cells to continue to grow
by evading the restrictions imposed by the lack of oxygen.

The findings were recently published in Cell Systems by Kshitiz, an assistant professor in the Department of Biomedical Engineering, who collaborated
with researchers Chi V.
Dang of Johns Hopkins University and Andre Levchenko of Yale University.

About a decade ago, researchers observed a strange phenomenon
while looking at cancer cells deprived of oxygen.

"As tumors grow and get bigger, they run out of oxygen, creating new blood vessels
," Kshitiz said.
In the absence of oxygen, cells should slow down their growth, but of course, the cancer will continue to get bigger
.
This is an unsolved puzzle
.
”

The researchers determined that a small percentage of cells were "cheating" — or rewiring their signals to allow them to divide and grow
.
Unraveling the mystery of how cells deceive — and how this phenomenon applies to cancer diagnosis — soon became the focus of
researchers' work.

Under hypoxic conditions, cells stabilize a protein called HIF-1, which is the main regulator of oxygen response in cells
.
When oxygen drops, HIF-1 signaling becomes high, putting cells into a non-functioning state
.
HIF-1 can instruct cell division mechanisms to stop working, initiate anaerobic respiration with large amounts of glucose, and cause cells to secrete proteins that direct blood vessels to themselves
.

In this study, the researchers noticed that a small group of cells did not stabilize HIF-1, but instead caused the protein to oscillate — moving
it up and down.
When HIF-1 oscillates, from top to bottom to top, cells can escape the pause
imposed by HIF-1.
In this way, these oscillating cells cheat and continue to divide, despite the very low
oxygen content.

"Finding scammers in a group of cancer cells that are themselves also tricking normal cells is interesting
on many levels," Kshitiz said.
We have observed oscillations in many systems, but oscillations in HIF-1 activity have not been recorded before, which is indeed noteworthy," Levchenko added
.
"We are particularly interested in how such oscillations are identified as triggering signals for specific genes
.
"

In addition, the researchers found that cancer cells can communicate with each other, allowing cells to sense the density
of other cells.
When HIF-1 is elevated due to lack of oxygen, cells produce energy
without oxygen.
Its byproduct is lactate, which can cramp
during exercise if the muscles are not oxygenated enough.
Cancer accumulates large amounts of lactate
in the environment.
Kshitiz, in collaboration with UCSF researcher Junaid Afzal, identified the detailed mechanism
that causes lactic acid to destabilize HIF-1.

"The excess lactic acid forces the cells to respire, even when oxygen is scarce, which leads to degradation of HIF-1 in lysosomes, which are circulating centers in cells," Kshitiz said
.

However, the question remains – do these microscopic observations make sense in real cancer cases? Current technology does not yet provide an effective way to test these predictions in animal experiments, let alone in humans
.

Kshitiz, along with Yasir Suhail, a postdoc in the lab at the University of Connecticut's School of Health, used the newly discovered information to study the genetic makeup
of different cancers that occur in humans.

"Our findings are truly shocking," Kshitiz said
.
"Most genes behave as expected, but there is a group of genes that behave the opposite as expected in the
absence of oxygen.
It doesn't make much sense; Why do genes that are turned on during hypoxia turn off when hypoxia oscillates? Apparently something is working
.
”

To further understand, Soherre studied these genes in all human cancers and found a common phenomenon
.
In most cancers, genes turned off by oscillations are turned off — suggesting that oscillations at HIF-1 levels may lower tumor suppressor genes and promote growth
in most cancers.

Kshitiz said: "The most interesting aspect is the prevalence of this phenomenon in all
cancers.
The effect appears to be pan-cancer, not any kind of cancer
.
”

This study sheds light on this unique phenomenon, answering several difficult questions about cancer while opening up new routes
of scientific inquiry.

"This is a large collaboration across many institutions and proves that deep scientific questions require the integration of multiple types of expertise to achieve
," Kshitiz said.