New Study Offers Insights Into Intratumoral Cancer Cell Intravasation

California researchers think they may have discovered why some cancers may reoccur after years in remission. In an article published in the journal Cell Reports, they demonstrate how invasive tumors may begin sending out tumor cells far earlier than previously thought.

Scientists at The Scripps Research Institute (TSRI) report that tumor cells enter blood vessels within the tumor core and not in the invasive tendrils. The active entry of cancer cells into the circulation is known as intravasation. Until now, it has been considered a relatively late event in tumor development occurring after stromal invasion. Now, this team has found that intravasation may be initiated early during tumor development and proceed in parallel to or independent of tumor invasion into surrounding stroma.

This discovery challenges the long-held assumption that tumor cells enter the bloodstream only after they invade adjacent stroma and reach tumor-converging blood vessels. Instead, the researchers found that fewer than 10% of escaped cells intravasated from the stroma-invading sprouts.

“The actual process of cancer cell dissemination via hematogenous routes is a relatively under-studied process, but we finally have an answer as to where it takes place,” said study investigator Elena Deryugina, PhD, who is an Assistant Professor Assistant in the Department of Molecular Medicine at TSRI, La Jolla, California.

Typically, a solid tumor is more or less confined during stages 0 and I, but starts invading nearby tissues at stage II. It is believed that the tumor begins to send the cells to distant organs only after extensive invasion into the adjacent stroma at stage III. Stage IV is usually associated with metastases. The researchers suggest it may be time to rethink how stages are defined.

The researchers applied direct and unbiased intravasation scoring methods to two histologically distinct human cancer types in live animal models. They were surprised to find that intravasation occurred almost exclusively within the tumor core. They also found this process involved intratumoral vasculature. For this investigation, the team used cancer cell lines generated from human fibrosarcoma and carcinoma tumors.

To find out exactly where escaping cells come from, the scientists tagged human tumor cells with a florescent protein to distinguish them from the cells of a tumor-bearing animal. Using high-resolution confocal microscopy techniques, the researchers mapped in 3D all blood vessels across entire tumors, from the tumors’ dense cores to their invasive tendrils.

These new findings may help explain why patients with early-stage tumors still have a risk of developing metastatic disease. The researchers found that levels of epidermal growth factor receptor (EGFR) could be a good indicator of whether tumor cells would intravasate. EGFR appeared to regulate a tumor’s ability to induce blood vessels that support cancer cell proliferation. Deryugina said the data point toward harnessing EGFR activity in cancer patients early rather than later.