at Dana-Farber Cancer Institute have found in a new study that cells lining
milk ducts in the breast may trigger spread of a common form of breast cancer.
to the study, when a form of cancer that begins in the milk ducts of the breast
invades neighbouring tissue to spread to other parts of the body, the cause
lies not in the tumour cells themselves but in a group of abnormal surrounding
cells that cause the walls of the duct to deteriorate like a rusty pipe.
findings might lead to screening tests to determine whether the disease, known
as ductal carcinoma in situ, or DCIS, is likely to spread beyond the ducts,
based on genetic abnormalities in cells in the ducts' lining.
discovery also sets the stage for treatments that, by targeting these
abnormalities, shore up the duct walls and keep the cancer contained.
whose DCIS has invaded the ducts are known to have a greater chance of
metastasis, or spreading disease. But it hasn't been clear what causes the
transition from a localized cancer to invasive disease," said the study's
senior author, Kornelia Polyak, MD, PhD, of Dana-Farber.
study demonstrates that in DCIS of the breast, and potentially in other cancers
that originate in duct tissues, the answer may lie in the tumour's
microenvironment -- the cells and tissue that surround the cancer," Polyak
study, Polyak and her colleagues focused on myoepithelial cells, which form
part of the lining of the milk ducts and are involved in breast development, as
well as impeding the growth and invasiveness of some cancer cells.
In order to
study what role, if any, these cells play in DCIS, the researchers worked with
a specially engineered line of cells known as MCFDCIS.
injected in laboratory animals, the MCFDCIS cells formed DCIS-like tissue that
developed into invasive tumours, providing a good model of what happens in
researchers injected both MCFDCIS and myoepithelial cells into the mice, DCIS
tumours arose, but they were confined to the ducts.
injected MCFDCIS cells and fibroblasts, cells found in milk ducts and other
connective tissue, the resulting DCIS tumours broke into the walls of the
findings made it clear that fibroblasts promote tumour growth and invasion, and
normal myoepithelial cells suppress it," Polyak said.
when certain genes in the myoepithelial layer become under- or overactive, the
layer breaks down and disappears, enabling tumour cells to escape.
In order to
identify which genes are affected and what causes their activity level to
change, researchers surveyed the activity of thousands of genes in
myoepithelial and DCIS cells using advanced SAGE (Serial analysis of gene
tumours trespass into the lining of the ducts, the activity level of several
myoepthelial cell genes is abnormal -- specifically the TGF Beta, Hedgehog, and
p63 genes as well as genes that help myoepithelial cells stick to 'basement'
cells on the ducts' outer layer.
is a cacaphony of erratic signals and haywire activity that prevents
myoepithelial cells from fully maturing and forming an effective barrier to
found a constant, complex interplay of signals among these genes, both within
myoepithelial cells themselves, and between myoepithelial cells and their
neighbours," Polyak said.
presence of DCIS causes the pattern of signals to change significantly,
upsetting the normal development of myoepithelial cells. The myoepithelial
cells fail to fully differentiate" -- act as true 'gatekeepers' for DCIS --
"leading to the disappearance of the myoepithelial layer and the beginning
of tumour invasion," Polyak added.
to Polyak, the discovery suggests that by scanning myoepithelial tissue for
abnormalities in these key genes, doctors might be able to identify which women
with DCIS have the greatest risk of cancer spread.
provides numerous targets for future drugs aimed at restoring the normal
balance of signals among these genes.
results highlight the importance of the microenvironment in breast tumour
progression. And they suggest that therapies that target the interactions of
tumour cells with their surroundings may offer a better way of inhibiting
tumour progression than those that focus on the tumour epithelial cells
alone," Polyak said.
is published in the May 6 issue of Cancer Cell.