New laboratory findings at the University of Illinois at Chicago suggest that what lies outside cancer cells is at least as important as the genes inside in explaining a tumor's malignancy.
The molecules that surround a cell 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, according to a study published in the April issue of the American Journal of Pathology.
An editorial in the same issue of the journal says the study represents what it calls a paradigm shift in our understanding of how malignant cells operate. The findings are expected to yield new diagnostic and therapeutic tools in the battle against cancer.
Initial experiments at UIC found 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 that recur throughout the genome thoroughly chewed up the DNA from normal cells. In contrast, the enzyme only partially broke up the DNA from less aggressive tumors, and it 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," said Andrew Maniotis, assistant professor of pathology and lead author of the study.
"We tested a range of cells -- from connective tissue, breast tissue, the kidney and the colon -- as well as biopsy tissue. The results were always the same," added Robert Folberg, head of pathology and a co-author of the paper. "The more invasive the cancer, the more resistant its DNA was to the enzyme."
But the question was why.
The answer lies in the cells' immediate environment, called the extracellular matrix, a rich mix of molecules once thought to be biologically inert.
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.
"Tests showed that in the presence of laminin, the activity of close to 1,000 genes was affected," Folberg said.
Additional experiments demonstrated 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 -- really, a stiff wire with component nucleotides -- 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 -- microtubules, actin and intermediate filaments -- not only did the cell's shape change, but its DNA took on new contours. Segments of DNA became buried inside the wad of genetic material, inaccessible to enzyme digestion.
"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," Maniotis said.
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.
The researchers also believe that their findings suggest new therapeutic strategies for combating cancer.
"Many current forms of chemotherapy target DNA directly and are associated with significant side effects," Folberg said. "We're developing methods of manipulating the genome that may be non-toxic and still highly effective."
Other researchers involved in the study were Klara Valyi-Nagy, John Karavitis, Jonas Moses, Viveka Boddipali, Ying Wang, Rafael Nunez, Suman Setty, Zarema Arbieva, all from UIC, and Mina Bissell, from the Lawrence Berkeley National Laboratory. Maniotis and Folberg are both members of the UIC Cancer Center.
The study was supported by grants from the National Eye Institute of the National Institutes of Health and the U.S. Department of Energy.
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