Oxygen deficiency causes tumors to change strategy

As soon as a tumor becomes hypoxic (deficient in oxygen), it changes its metastasis strategy: instead of producing long strands of connected cells, the tumor produces single cells that move through the body.

In experiments with cancer cells from humans and mice, Peter Friedl, theme Cancer development and immune defense and Steffi Lehmann of ETH Zurich discovered that the cell protein HIF-1 plays a key role in this process. The study provides new insight into how cancer spreads in the body and will be published in the February issue of Current Biology.

A metastasizing tumor has several options. It can disseminate by forming strands that grow into the naturally occurring spaces in the surrounding tissues. This is known as the collective program. But the tumor may also produce individual cells that live independently, which can spread through the bloodstream. For a long time it was unclear how the tumor makes the ‘decision’ to shift from a collective program to the individual-cell program. The research team, led by Peter Friedl and Steffi Lehmann, has discovered a major trigger for this transition: hypoxia. 

Hypoxic conditions
The researchers grew various types of cancer cells from humans and mice in the lab under normal conditions (21 percent oxygen) and hypoxic conditions (0.2 percent oxygen). Under normal conditions, the tumor produced strands of cells, and only a few individual cells escaped. Under hypoxic conditions, many more individual cells were released. In terms of shape and characteristics, these individual cells are similar to leukocytes, a type of white blood cell. Peter Friedl: “Hypoxia not only encourages cell migration, but also affects how the cells migrate.” 

Escape signal
Hypoxia is a normal phenomenon in tumors. A growing tumor is actually not connected to the blood vessels, which means the cancer cells may not have enough oxygen. To continue to grow, the tumor needs to generate blood vessels. This process is called angiogenesis. The cell protein HIF-1, which affects the transcription (reading) of DNA, plays an important role in angiogenesis. But it now appears that HIF-1 is also important for the transition in metastasis program. Suppression of HIF-1 in the cancer cells in the laboratory shifted the individual-cell program back to the collective (branching) program. 

A dandelion that has gone to seed
It is likely that the individual-cell program helps the tumor to metastasize over a greater distance. In fact, the metastasizing tumor cell uses a similar strategy to that of white blood cells. Although the researchers found no evidence that individual-cell metastases were more effective in colonizing organs in the body, once a location was colonized, the cells grew into new tumors more quickly. Peter Friedl: “Hypoxia in tumors is an important mechanism that temporarily causes a rapid increase in the number of metastatic cells. You could compare it to blowing on a dandelion that has gone to seed.”

Image: tumor strands (blue cells) from which individual cells become detached.
Photograph: Steffi Lehmann and Peter Friedl