Sci. Aging Knowl. Environ., 26 January 2005
Vol. 2005, Issue 4, p. nf8
[DOI: 10.1126/sageke.2005.4.nf8]


Led Astray

Worn-out cells prod healthy ones toward cancer

Mitch Leslie

Cells that have lost the ability to divide are like those bad kids your mother warned you to avoid. They corrupt young cells, disrupting the growth and specialization of fresh tissue, according to new research. Rising numbers of these stagnant cells might explain why our bodies don't work as well in our golden years.

After cells have undergone many divisions, they typically slip into a semiretirement called replicative senescence, in which they can no longer duplicate (see "Dangerous Liaisons"). Signals such as shrunken telomeres, the protective caps at the ends of chromosomes, trigger senescence. Shutting down cells with diminutive telomeres makes sense because they're susceptible to chromosomal chaos that promotes cancer. But even from their rocking chairs, the stalled cells can make trouble. For example, in 2001 cell and molecular biologist Judith Campisi of Lawrence Berkeley National Laboratory in California and colleagues showed that senescent cells could spur genetically damaged but noncancerous cells to form tumors (see "Faustian Bargain"). The researchers wondered whether senescent cells also harm genetically unscathed ones.

The scientists cultured a human breast cell line along with either senescent or youthful connective tissue cells, which coax mammary cells to specialize. Both types of connective tissue cells spurred breast tissue to form bulb-shaped structures like those that secrete milk, but the bulbs grown with senescent cells were larger and misshapen. They also carried more of a protein that accumulates when cells duplicate their DNA. Culturing a different cell line revealed that bulbs that grew with nonsenescent cells pumped out about twice as much of a milk protein as did bulbs reared among stagnant cells. Together, the results suggest that senescent cells upset the architecture and function of mammary tissues.

At puberty, networks of ducts spread through breast tissue. The team simulated this process in culture by growing clumps of mouse mammary cells. They found that senescent cells elicited more branching and longer extensions from the clumps than did normal cells. Thus, exposure to senescent cells could boost the ability to infiltrate neighboring tissues, a characteristic of cancer. Previous work had shown that senescent cells exuded much more MMP-3, a protein that sparks branching, than did their nonsenescent counterparts. In the current study, the researchers discovered that blocking MMP-3 in stagnant cultures trimmed branch formation and elongation. By increasing cells' growth and "invasiveness," stagnant cells undermine some checks on cancer, says Campisi, and they could instigate other problems. The cells accrue as we grow older, and their increased abundance could explain why aged tissue tends to be disorganized and doesn't perform as well as younger tissue.

The work "is very important and helps to raise our awareness of the activities of senescent cells as a major pathogenic factor," says cancer researcher Igor Roninson of the Ordway Research Institute in Albany, New York. The story is more complicated, he notes, because not all senescent cells are antisocial rogues. Research from his lab and others indicates that some of the cells emit cancer-fighting compounds. Nonetheless, he says, drugs that block harmful releases from senescent cells should protect their impressionable neighbors from a bad influence.

January 26, 2005
  1. S. Parrinello, J.-P. Coppe, A. Krtolica, J. Campisi, Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci., 18 January 2005 [e-pub ahead of print]. doi:10.1242/jcs.01635 [Abstract/Free Full Text]
Citation: M. Leslie, Led Astray. Sci. Aging Knowl. Environ. 2005 (4), nf8 (2005).

Science of Aging Knowledge Environment. ISSN 1539-6150