New insight into how cancer cells overcome lack of oxygen

Duncan Stewart

Amato Giaccia

A tiny RNA plays a big role in the initiation and growth of pancreatic and other tumors, report researchers at the Stanford University School of Medicine. The snippet of genetic material blocks the expression of normal metabolic genes and allows the cancer cells to channel their energy into surviving what can be a tough, oxygen-starved environment.

“These cells are not going to spend energy to make unnecessary proteins,” said cancer biologist Amato Giaccia, PhD. “By down-regulating these genes, the microRNA probably makes the cells able to adapt more quickly to the lack of oxygen that develops in a growing cancer.”

MicroRNAs are small, single-stranded RNA molecules about 22 nucleotides long that regulate gene expression. They’ve been gaining increasing recognition during the past few years for their previously unsuspected roles in regulating many cellular functions.

Because of the unregulated nature of their growth, even tiny tumors a few cells in diameter can struggle to get enough fuel to support themselves. That’s why many cancer cells also express molecules called angiogenesis factors to spur the growth of new blood vessels toward and into the tumor. Still, most solid tumors continue to struggle with low oxygen levels—a condition called hypoxia—as they grow.

Giaccia’s lab has focused for many years on understanding how tumors adapt to their microenvironment, including hypoxic conditions. He is the Jack, Lulu and Sam Willson Professor and professor of radiation oncology. He is also a member of Stanford’s Cancer Center and the senior author of the research, published in the journal Molecular Cell on Sept. 25. Giaccia and his lab members collaborated with researchers at the University of Texas’s M.D. Anderson Cancer Center and Southwestern Medical Center on the study.

The researchers were investigating whether microRNAs are activated in response to a well-known hypoxia-inducible gene, HIF1. HIF1 binds to the upstream regions and ramps up the expression of a variety of genes involved in metabolism and tumor growth. They found that a microRNA previously implicated as a hypoxia-responder, called mir-210, was reliably expressed at high levels in every cell line they tested in the presence of HIF1, but not in lines in which HIF1 was absent. They also identified an HIF1 binding site in the upstream promoter region of mir-210, further confirming that mir-210 is specifically expressed in response to HIF1.

Next they searched for genes whose expression might be affected by mir-210.

“We thought that mir-210 might regulate other genes involved in hypoxia,” said Giaccia. “But instead it was affecting the expression of genes involved in normal metabolism.”

Mir-210 binds to the upstream regulatory region of these genes and derails their expression. Coupling the expression of hypoxia genes with the down-regulation of so-called “normoxia” genes allows the cell to fine-tune its metabolic expectations much like fiddling with the bass and treble controls on your home stereo.

This isn’t the first time that mir-210 has been implicated in human tumor development. It has been found overexpressed in many tumor types, and its expression in breast cancer patients seems to correlate with a poorer outcome. Therefore, the researchers were curious to see what effect it would have on human cancer cells transplanted into laboratory mice. But when they engineered a human pancreatic cancer cell line to express mir-210, they found that the modified cells now took much longer to establish tumors in the mice than did the unmodified cells.

“It affected very dramatically the initiation of tumor genesis,” said Giaccia. “But once the tumors were formed, it wasn’t that important.”

The researchers speculate that the role played by mir-210 varies according to the developmental stage of the tumor. “It’s clear that there may be additional functions of mir-210 that we haven’t yet identified,” said Giaccia. His lab intends to further categorize the genes affected by mir-210 and to develop a cell or animal model in which the mir-210 gene is missing or destroyed.

In the meantime, they point out that because mir-210 is released into the blood of patients with pancreatic cancers it may one day serve as a useful prognostic indicator as to disease course or therapeutic effectiveness.

In addition to Giaccia, Stanford researchers involved in the work include Xin Huang, PhD; Quynh-Thu Le, MD; Ricky Tong, PhD; Scott Welford, PhD; and Kevin Bennewith, PhD, who is now a research scientist at the British Columbia Cancer Research Centre in Vancouver. The research was funded by the National Institutes of Health.