The road to metastasis

Metastasis: how cancer cells make their way to blood vessels

LifeSciencesToday based on MIT materials: Paving the way for metastasis

A new study by scientists from the Massachusetts Institute of Technology (MIT) shows how cancer cells take their first steps from the primary tumor to the blood vessels. This spread, known as metastasis, is responsible for 90 percent of cancer deaths.

Studying mice, the researchers found that cancer cells with a special form of the Mena protein – Mena***INV (Mena invasive) – are able to change their environment, thereby facilitating their migration into blood vessels and spreading throughout the body. In addition, they showed that high levels of this protein correlate with metastases and earlier death of breast cancer patients.

The ability to block this protein can help prevent metastasis, says MIT biology professor Frank Gertler, a researcher at The David H. Koch Institute for Integrative Cancer Research.

"This is something, I think, that may prove very promising, because we know that with the genetic removal of MenaINV, tumors become non–metastatic," says Professor Gertler, head of the study, the results of which are published in the journal Cancer Discovery (Oudin et al., Tumor cell-driven extracellular matrix remodeling enables haptotaxis during metastatic progression).

In order for a tumor to metastasize, its cells must first become mobile, and then migrate through the surrounding tissues into the blood vessels. In a new study, a team from MIT found that cancer cells follow in the footsteps of fibronectin, a protein that is part of the extracellular matrix that provides structural support to surrounding cells. In particularly high concentrations, fibronectin is found at the edges of tumors and near blood vessels.

"Cancer cells in the tumor environment constantly face differences in the concentration of fibronectin, and in order to reach blood vessels, they must be able to move from low to high concentrations," explains the first author of the article Madeleine Oudin, a postdoctoral fellow at the Koch Institute.

MenaINV, an alternative form of the normal Mena protein, plays a key role in this process. MenaINV includes a segment that is not present in the usual form of this protein, and this allows it to bind more strongly to a receptor known as integrin alpha-5, located on the surface of tumor and nearby supporting cells and recognizes fibronectin.

Binding of MenaINV to integrin alpha-5 stimulates interaction with the same fibronectin protein receptor. The folded, as a rule, fibronectin protein, when binding to the cell surface, stretches into long bundles. This stimulates the organization of collagen, another extracellular matrix protein, into rigid fibrils extending from the edges of the tumor.

These structures, usually found in more aggressive tumors, essentially pave the way for cancer cells to blood vessels.

In the experiment, mouse cells with an invasive form of Mena better recognized high concentrations of fibronectin and migrated towards them, moving along the collagen pathways, while cells without MenaINV did not move towards higher concentrations.

The process of metastasis in mouse tumors, where tumor cells (green) helped organize collagen into aligned fibers (blue), providing structural support for the migration of cancer cells. This helps the cells to penetrate into the blood vessels (red), which ultimately leads to the formation of metastases in other organs. (Photo: Madeleine Oudin and Jeff Wyckoff)

The researchers examined data from breast cancer patients and found that high levels of MenaINV and fibronectin are associated with metastases and early death. Meanwhile, no connection between the usual form of Mena and early death has been established.

Gertler's laboratory has previously developed antibodies capable of detecting normal and invasive forms of Mena, which are currently being refined for testing biopsy samples of patients. Such tests can help doctors determine whether a patient's tumor is predisposed to metastasis, and possibly in prescribing therapy. In addition, scientists can develop drugs that inhibit MenaINV, which can help in the treatment of cancer or prevent its metastasis.

Now, researchers hope to study how MenaINV may contribute to the development of other cancers. Preliminary studies show that it plays a similar role in lung and colon cancer. In addition, scientists are investigating how the choice between two forms of the Mena protein is regulated and how other extracellular matrix proteins can contribute to the migration of cancer cells.

Portal "Eternal youth" http://vechnayamolodost.ru  18.03.2016