Tumors form advance teams to ready lungs for spread of cancer

Cancer metastasis requires tumor cells to acquire properties that allow them to escape from the primary tumor site, travel to a distant place in the body, and form secondary tumors. But first, an advance team of molecules produced by the primary tumor sets off a series of events that create a network of nurturing blood vessels for arriving primary tumor cells to set up shop.

In lung cancer, the formation of that niche likely involves and moderate levels of VEGF and other molecules that promote the formation of new blood vessels, or angiogenesis. But little is known about how the local lining, or endothelial, cells are activated at the niche.

Sandra Ryeom, PhD, assistant professor of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, and colleagues, found that the signaling protein calcineurin upregulates another molecule, Ang-2 that promotes the needed angiogenesis. Hyperactivation of calcineurin in genetically altered mice that lack an inhibitior of calcineurin signaling leads to increased lung metastases. Conversely, inhibiting calcineurin or Ang-2 blocked metastases in of the mice. The findings are published this week in Cell Reports.

The findings may help shed light on the underpinnings of common patterns, such as the tendency of prostate cancer to spread to the bones, or melanoma to the brain.

"We demonstrated that the calcineurin pathway is activated specifically in lung endothelium prior to the detection of that preferentially and spontaneously metastasize to the lung from our experimental model of flank tumors in mice," says Ryeom.

Also, increased VEGF levels specifically in the lung, and not other organ microenvironments, trigger a threshold amount of calcineurin signaling that activates the Ang2 gene in lung endothelial cells. What's more, they showed that overexpression of the Ang-2 receptor prevents activation of the lung endothelium and inhibits lung metastases in their mouse models.

"Our studies provide insights into the mechanisms underlying angiogenesis in the pre-metastatic niche and offer new targets for lung metastases," she says.

Because calcineurin acts on the pathways that set up sites of metastasis away from the primary tumor sites, it could be a potential target for future cancer therapies; however it is also active in the immune system. In fact, calcineurin is inhibited by cyclosporine, which is used to combat transplant rejection, so using these types of drugs would be tricky for cancer unless they can be targeted specifically towards .

Ongoing studies in the Ryeom lab are investigating whether is important for metastases in other organs or whether this pathway is specific for lung metastases.

add to favorites email to friend print save as pdf

Related Stories

Why do people with Down syndrome have less cancer?

May 20, 2009

Most cancers are rare in people with Down syndrome, whose overall cancer mortality is below 10 percent of that in the general population. Since they have an extra copy of chromosome 21, it's been proposed that people with ...

Recommended for you

XenOPAT, mouse models for personalized cancer treatment

1 hour ago

On September 8th, the company XenOPAT SL, a spin-off of the Institute of Biomedical Research (IDIBELL) and the Catalan Institute of Oncology (ICO) was established with the aim of bringing the company the latest scientific ...

Gene linked to development of skin cancer in mice

3 hours ago

(Medical Xpress)—New research on an enzyme linked to cancer development shows that 37 percent of mice that produce excessive quantities of the enzyme developed skin tumors within four to 12 months of birth, ...

User comments