By Cather­ine Zan­donella, Office of the Dean for Research

A new study has found that can­cer cells appear to exchange lead­ing roles as they migrate out of a tumor in the early stages of inva­sion, or metas­ta­sis, of other sites in the body. Metasta­tic can­cer accounts for more than 90% of cancer-related deaths.

A team led by Robert Austin, pro­fes­sor of physics at Prince­ton Uni­ver­sity, found that indi­vid­ual can­cer cells take turns as trail­blaz­ers when they carve their way through the dense wall — known as the extra­cel­lu­lar matrix — that stands between a tumor and the blood ves­sels which can carry the cells to other parts of the body.

The researchers also found that the cells leave the tumor in search of food, since cells that had plenty of avail­able nutri­ents did not migrate. The find­ing rein­forces the hypoth­e­sis that metas­ta­sis occurs when tumors become so densely packed that blood ves­sels can­not pen­e­trate the inte­rior and can­cer cells must migrate to survive.

The researchers included first author Liyu Liu of the Chi­nese Acad­emy of Sci­ences; Guil­laume Duc­los of the National Cen­ter for Sci­en­tific Research in Paris; Bo Sun, Jeongseog Lee, Amy Wu, Howard Stone and James Sturm of Prince­ton Uni­ver­sity; Yoon­seok Kam and Robert Gatenby of H. Lee Mof­fitt Can­cer Cen­ter in Tampa; and Eduardo Son­tag of Rut­gers Uni­ver­sity. The arti­cle appeared in the Pro­ceed­ings of the National Acad­emy of Sciences.

To study can­cer cell behav­ior, the researchers con­structed a small cham­ber with three com­part­ments arranged like floors in an apart­ment build­ing. On the bot­tom floor was a well of glu­cose, the pre­ferred food for metasta­tic cells. The mid­dle floor con­tained a dense layer of col­la­gen, a pro­tein that makes up the extra­cel­lu­lar matrix that sur­rounds tumors. On the top floor they placed metasta­tic can­cer cells, which were labeled with flu­o­res­cent dye for vis­i­bil­ity. They trained a micro­scope and cam­era on the chamber.

Through the micro­scope, the researchers filmed the can­cer cells as they moved down through the cham­ber toward the glu­cose. The researchers found that a sin­gle cell would become the leader for some time, then drop back as another cell took the lead in what the authors term a “col­lec­tive inva­sion strat­egy.” They also found that the col­la­gen was pushed aside, leav­ing a wake in which cells behind the leader could travel.

Because the col­la­gen is very dense, the cells must expend a lot of energy to reach the glu­cose, and indeed the researchers found that cells with­out a need for glu­cose did not bother to bur­row down into the col­la­gen. The researchers used col­la­gen with a den­sity sim­i­lar to that of human breast tissue.

The study adds to the grow­ing under­stand­ing of metas­ta­sis and could serve to assist researchers in devel­op­ing strate­gies for its prevention.

Liyu Liu, Guil­laume Duc­los, Bo Sun, Jeongseog Lee, Amy Wu, Yoon­seok Kam, Eduardo D. Son­tag, Howard A. Stone, James C. Sturm, Robert A. Gatenby, and Robert H. Austin. Min­i­miza­tion of ther­mo­dy­namic costs in can­cer cell inva­sion. PNAS Jan­u­ary 14, 2013 201221147.

Read the paper (open access).

This work was sup­ported by the National Sci­ence Foun­da­tion and the National Can­cer Institute.