Spreading aggressive traits
between cancer cells

Until recently, researchers thought that cell division was the only way for an aggressive cancer cell to pass its traits along. New evidence is showing that cancers can become more dangerous by exporting aggressive traits to neighboring cells via exosomes. These small packages — bubbles — of membrane released into the extracellular environment hold pieces of host RNA, DNA and proteins. Now, a new study has shown that exosomes also can hold and transfer integrin molecules known to promote metastasis in several cancers.

“This is an important addition to the research showing that tumors have novel ways of spreading aggressive traits,” says senior author Lucia Languino, a researcher at the Sidney Kimmel Cancer Center at Thomas Jefferson University.

Integrins are transmembrane molecules that tether cells to one another and to the extracellular matrix that surrounds them. They often are altered during a cell’s progression into a cancerous state, allowing the cell to detach from its surroundings and become more mobile and more likely to enter the bloodstream and metastasize to distant sites in the body. They also act as receptors, relaying signals that alter the gene expression involved in cell survival and division.

Earlier research showed that the integrin αvβ6 is abundant in prostate cancer cells but not normal prostate cells. It appears to promote proliferation and migration by activating intracellular signaling molecules and may be involved in promoting metastasis to the bone. It also may activate the production of cytokines that promote metastasis.

Because of its role in prostate cancer, Languino, first author Carmine Fedele and colleagues investigated whether this integrin might be transferred between cells via exosomes. In a study reported recently in the Journal of Biological Chemistry, the researchers examined the exosomes released from prostate cancer cell lines known to express the αvβ6 integrin and found that the exosomes were enriched with this integrin. The research also was supported by the work of Amrita Singh, a graduate student in Languino’s lab, and the collaboration of professor Renato Iozzo.

To determine whether neighboring cells took up the αvβ6 exosomes, the researchers used a cell line that lacked the ability to produce its own αvβ6 integrin. They incubated αvβ6-lacking cells with PKH26 Red-labeled αvβ6 exosomes and showed that the cells efficiently internalized the exosomes. They also determined by FACS analysis that the cells expressed the integrin molecule on their surface.

Finally, to test whether these newly αvβ6 integrin-expressing cells gained new, more metastatic-like functions, Languino and colleagues plated the cells on a surface containing αvβ6 ligands. The team noted that cells incubated with αvβ6 exosomes were able to adhere to the surface and migrate in a dose-dependent fashion, whereas cells incubated with exosomes expressing the β6 subunit alone did not adhere and migrate efficiently.

“The research suggests that the αvβ6 integrin can transfer between prostate cancer cells,” says Languino. “In theory, inhibiting the αvβ6 integrin could reduce the chances of prostate cancer metastasis, and targeting exosomes could be an important part of achieving that goal.”

Edyta Zielinska Edyta Zielinska is is a science writer and media relations representative at Thomas Jefferson University.