The Structure Is the Message 

What if cancer is triggered by changes outside the cell?

Mutation does not always mean cancer. If you sampled cells from any woman's breast, Dr. Mina Bissell says, you would find a scattering of premalignant or even malignant cells. Despite these mutations, in seven out of eight women, those cells would be sitting there quietly, not causing trouble. Yet in the eighth woman, a few cells would progress to cancer. Why?

The answer, Bissell thinks, has to do with the very architecture of our bodies' organs.

The reason our internal organs aren't gelatinous blobs is because the cells sit on a latticework structure called the extracellular matrix. For years, researchers thought that the matrix was not much more than scaffolding. But Bissell's research has shown that this superstructure is actually in constant two-way communication with the cell's DNA, telling it both where it is, and how to behave as part of the larger tissue. In return, the matrix is modified by the genome. It is a prodigious idea: that the cell knows its function because of its orientation within a complicated 3-D architecture. "The structure is the message," she says.

Bissell believes that if something in the cell's microenvironment changes so that the cell and the extracellular matrix no longer exchange messages properly, the cell becomes disoriented, and essentially "forgets" where it comes from and what it is supposed to do. It goes from being a neatly organized cell, with a distinct top and bottom and a specific function, to being a disorganized mess that eventually breaks all the rules. Without the matrix maintaining order, cells that already had tumor-causing potential can begin proliferating, and cells with no previous mutation can become genomically unstable. "It is precisely when the cell in your nose, the cell in your breast, the cell in your skin doesn't know that it is supposed to stay put that it becomes cancer," Bissell says.

She believes this is why only a few cells overgrow and form tumors, not all of them, and that this is why a cell — even one with an inborn mutation — can remain well-behaved for years, and then suddenly go berserk if it stops getting the right signals. As long as the microenvironment can keep it in check, it won't become a tumor. But if the extracellular matrix breaks down, the cell loses its orientation and therefore its identity. "You can have mutation, mutation, mutation until you are blue in the face, and if the structure doesn't go," Bissell says, "you don't get cancer."

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