A protein secreted by common cancer types makes blood vessels leakier to allow metastatic tumors to form in the lungs, according to a study led by investigators at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center. The findings were published on Aug. 5 in Nature Cancer and could lead to new ways of monitoring and reducing lung metastasis risk in cancer patients.
The research team sought to explain how some tumors enhance their ability to metastasize to the lungs by secreting tiny capsules and particles known as extracellular vesicles and particles (EVPs), which carry proteins, DNA, and other molecules. These EVPs are secreted by virtually all cells for signaling purposes, but tumors have adapted them for their own benefit. In this study, researchers identified a protein called integrin alpha-5 as the cargo within tumor-derived EVPs that promotes lung blood vessel leakiness and facilitates lung metastasis across several types of cancer.
"These findings help us understand one of the mechanisms underlying lung metastasis, so that we can start to think about ways to detect and block it to improve outcomes for patients," said Dr. David Lyden, senior author of the study and Stavros S. Niarchos Professor in Pediatric Cardiology at Weill Cornell Medicine.
The role of tumor cell-secreted EVPs has become more widely recognized over the past two decades as an important aspect of cancer biology. According to Lyden's lab and others, tumors use EVP molecular cargo both locally—creating a pro-tumor environment—and systemically—preparing distant organs for potential metastasis. Tumor EVPs are now seen as promising targets for therapies as well as detection technologies such as liquid biopsies based on blood sample analysis.
In previous work, Lyden's group found that certain tumor EVPs facilitate lung metastasis by making blood vessels leaky enough for circulating tumor cells to enter the lungs. The new study confirmed in animal models that cancers such as melanoma, osteosarcoma, and colorectal can trigger increased lung vessel leakiness via these secreted EVPs—even when injected into healthy mice without tumors present.
Further investigation revealed that these effects occur rapidly after EVP injection due mainly to interactions with immune cells called macrophages near lung blood vessels—but only when integrin alpha-5 is present within those vesicles. Integrin alpha-5 prompts macrophages to secrete IL-6, a pro-inflammatory protein causing endothelial cells lining nearby vessels to loosen up.
To determine if these results apply beyond animal models, researchers analyzed gene expression data from human tumors and found high integrin alpha-5 levels associated with poorer survival rates in several cancers including colorectal cancer. Patient samples from intermediate or advanced colorectal cases also released integrin alpha-5-containing EVPs capable of inducing vessel leakiness.
Researchers say these results reveal an important mechanism promoting metastasis in some cancers with possible clinical implications.
