Extracellular Matrix Affects Gene Behavior

New research shows that the molecules that surround a cell, known as the cellular matrix, play a crucial role in altering the packaging of its genome, opening it up to the machinery that allows genes to be expressed or closing it down.

This suggests that what lies outside cancer cells is at least as important as the genes inside in explaining a tumor's malignancy. Experiments at the University of Illinois at Chicago (UIC, USA) showed that the genetic material of cancer cells is knotted-up so that sections of DNA are highly protected from outside interference, unlike the DNA of healthy tissue. An enzyme that snips DNA at certain sequences recurring throughout the genome thoroughly chewed up the DNA from normal cells but barely touched the DNA from aggressive cancers like melanoma.

"In invasive cancers, segments of DNA are so twisted and compacted that the enzyme can't get access,” explained Dr. Andrew Maniotis, UIC assistant professor of pathology and lead author of the study. After testing a range of cells, including connective tissue and breast tissue, the researchers found that the results were always the same. "The more invasive the cancer, the more resistant its DNA was to the enzyme,” added co-author Dr. Robert Folberg, head of pathology.

When three cancer-causing genes were inserted into the nuclei of normal cells, the entire genome became resistant to enzyme digestion. The UIC scientists were able to induce exactly the same effect after just one edge of a normal cell came into contact with laminin, a component of the extracellular matrix.

Additional experiments showed that the molecules outside a cell exert their influence not by chemical means but mechanically, manipulating the skeletal framework of the cell and the proteins that envelop DNA. These proteins keep the string of DNA tightly compressed. If the proteins are removed, the genes spring out like a jack-in-the-box. When the researchers disassembled a cell's skeletal elements, not only did the cell's shape change, but its DNA took on new contours. Segments of DNA were buried inside the wad of genetic material, inaccessible to enzyme digestion.

The discovery that normal, benign, and malignant tissues respond differently to enzyme digestion could lead to a new diagnostic tool for distinguishing different types of tumors, said the researchers. "Medical research has for decades focused on finding the underlying genetic abnormalities that cause disease, but this work demonstrates that genes themselves are controlled by components outside the nucleus and these, in turn, are regulated by the cell's microenvironment,” observed Dr. Maniotis.




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University of Illinois at Chicago