Breast cancer: why wake up dormant cancer cells?

Breast cancer: why wake up dormant cancer cells?

Riddle dormant metastatic cells cancer of the breast and their exit from the latent state in many years, even decades, possibly solved. Scientists National Laboratory Lawrence Berkeley ( Lawrence Berkeley National Laboratory ) DOE (US Department of Energy) believe that the niche in which are dormant cancer cells , is the microenvironment surrounding the microvasculature - small blood vessels transporting blood to the tissues . Upon germination of these vessels produce their end portions of the molecule that turns dormant cancer cells in metastatic tumors.

A small but nevertheless significant number of patients with breast cancer tumor cells proliferate in the bloodstream of the breast to other organs, where they can not be clinically detectable in a latent state for a long period of time. Predict when to begin their transformation into metastases (and will if at all) is very difficult, if not impossible.

"Our research shows that a stable microvascular network is a niche standstill, while the formation of new blood vessels is the trigger that stimulates the growth of micrometastatic" - says biologist Mina Bissell (Mina Bissell), PhD, in the laboratory which carried out the study . "Germination involves the development of vascular tissue, but if in the wrong place at the wrong time is a tumor cell, it falls under the influence of the factors contained in the terminal cells, and is also beginning to grow."
Dr. Mina Bissell is one of the experts in the field of breast cancer with a worldwide reputation. She and her research team member bioengineer Cyrus Ghajar (Cyrus Ghajar), PhD, - the senior authors of the article about the study, published in the journal Nature Cell Biology .

"Some patients may develop metastatic relapse within a few months, while others can live without distant metastases several years or even decades" - explains Dr. Bissell. "The recent discovery of tumor growth promoting microenvironments called metastatic niches that are generated in remote areas before or after the occurrence of these disseminated tumor cells may explain early recurrence of cancer cells. But that tumor cells do since spread before they become clinically detectable in late recurrent populations remained unknown. "
Mina Bissell (Mina Bissell) and Cyrus Ghajar (Cyrus Ghajar), may have solved the riddle of a long dormant disseminated tumor cells and found a molecular trigger their activation after many years or even decades of latency.

Mina Bissell (Mina Bissell) and Cyrus Ghajar (Cyrus Ghajar), may have solved the riddle of a long dormant disseminated tumor cells and found a molecular trigger their activation after many years or even decades of latency. (Photo: Roy Kaltschmidt)



Previous research by Dr. Bissell and her group demonstrated that it is the microenvironment that supports the state of rest as normal epithelial and dormant tumor cells creates a basement membrane - a thin layer of extracellular matrix proteins - Environmental breast cancer and other epithelial tissues. Given that breast cancer cells that propagate through the bloodstream to other organs - lung, bone marrow, brain and liver - must first pass through the basement membrane of microvessels, Ghajar and Bissell suggested that a major component of niches sleeping cells in distant organs may be basal membrane.

To test this idea, researchers have used two mouse models of metastatic human breast cancer and found dormant disseminated tumor cells on the membrane of the microvasculature of the lungs, bone marrow, and brain tissues. To determine whether a direct influence on the growth of breast cancer cells, endothelial cells - cells lining the inner surface of blood vessels - to create a unique pattern of organotypic lung microvascular recesses and bone marrow, where the endothelial cells formed in a culture structures similar corresponding blood vessels body. When the end portions of these structures were placed tumor cells has been reproduced that researchers observed in vivo .
At its organotypic models Bissell and her colleagues found that niche rest creates widespread microvascular networks in stable protein thrombospondin-1 , inhibits the growth of cancer cells. However, at the end portions of germination vessels thrombospondin-1 proteins are giving way to TGF-beta 1 and periostinu turning newly formed vessels in the metastatic niche that not only allows, but also accelerates the growth of cancer cells.

"Our research - the first in which a niche is described on the rest of cellular and molecular basis, and it is interesting that the culprit is the fabric, which we so often considered a passive observer - microvascular endothelium," - says Dr. Ghajar. "Moreover, we have shown that a key factor in most, if not all, biological processes is homeostasis. In this case, the destabilization of vascular endothelial niche destroys peace and promotes the formation of micro causing micrometastatic growth. "
Opening niches rest in the microvasculature of the basal membrane and an understanding of how these niches are metastatic to the newly formed vasculature, is of great importance for the development of future treatments for breast cancer.

"Our findings point the way to treatments aimed at the management of metastatic disease even before its manifestation," - said Ghajar. "Sleepers disseminated tumors may be time bombs, but now that we know some of their triggers, treatments can be developed to ensure that disseminated cancer cells remain dormant, or eradicate these cells before they can form metastases developed" .

"Our organotypic models demonstrate the capabilities of the microenvironment, indicating that normal cells in its native architecture naturally translate fully malignant genotypically aberrant tumor cells in a state of rest" - continued the scientist. "In the future, our models will be an effective tool for screening therapies that affect the state of rest tumors and metastases, as well as a platform for the disclosure of other biological mysteries that underlie this condition."

Currently Gadjar, Bissell and their research to find out whether the useful results for breast tumors, to other types of secondary tumors and tissues. Furthermore, they want to identify the unique mechanisms also transform tumor dormancy, but common in other tissues.