Defusing Cancer’s ‘Ticking Time Bombs’
A long-standing mystery in cancer is how cancerous cells move from being dormant to being metastatic. That is why, and more importantly how, do they go from being in a state of latency to one of active growth and movement to other parts of the body.
Now, a team of researchers from Lawrence Berkeley Laboratory (LBL), Berkeley, Calif., and the Weill Cornell Medical College, New York City, believe they have identified the microenvironment that contributes to the change of state of the cells. The work was done on breast tumor cells, but the researchers plan to apply their findings to other types of tumors and secondary tissues.
In the long term, the work could lead to “therapies aimed at managing metastatic disease before it even occurs – i.e. dealing with the ‘ticking time bomb’ that these dormant cells may be – either by ensuring that the cells remain in a dormant state or by uncovering a means to eradicate them before they can form full-blown metastases,” says Cyrus Ghajar, a bioengineer at Lawrence Berkeley Lab and team member on the project.
In a small, but significant number of breast cancer patients, cancerous cells can move through the bloodstream from breast tissue to secondary sites in other parts of the body where they remain in a dormant state, clinically undetected for an extended period of time before suddenly becoming metastatic. It has been difficult, if not impossible, to predict if and when metastases will occur.
The LBL/Cornell team identified the microenvironment surrounding microvasculature (small blood vessels that transport blood within tissue) as a niche where dormant cancer cells reside. When these blood vessels begin to sprout, the new tips produce molecules that transform dormant cancer cells into metastatic tumors.
“Our study reveals that a stable microvasculature constitutes a dormant niche, whereas sprouting neo-vasculature sparks micro-metastatic growth,” says LBL cell biologist Mina Bissell, in whose laboratory the work was performed. “Sprouting is meant to coincide with tissue growth, but if a tumor cell happens to be in the wrong place at the wrong time, then it comes under the influence of the factors deposited by tip cells and it starts growing.”
The research shows that dormancy is not a cell-autonomous state, Ghajar explains, “it is not a decision made exclusively by the cell itself, but done in concert with its microenvironment, with other cells, growth factors, e.”
Previous work by Bissell and her group showed that the basement membrane – the thin layer of extra cellular matrix proteins surrounding breast and other epithelial tissue – provides a microenvironment that induces quiescence in normal epithelial cells and dormant tumor cells alike. Given that breast cancer cells traveling through the bloodstream on their way to secondary sites where breast tumors metastasize most often – lung, bone marrow, brain and liver – must first pass through the basement membrane microvasculature, Ghajar and Bissell suspected that the basement membrane could be a major component of the dormant niche in distant organs.
To test the idea, the researchers used two mouse models of human breast cancer metastasis and found dormant disseminated tumor cells residing upon the membrane microvasculature of lung, bone marrow and brain tissue. To determine whether endothelial cells, the cells that line the interior surface of blood vessels, directly influence breast cancer cell growth, they then created unique organotypic models of lung and bone marrow microvascular niches, in which endothelial cells formed blood vessel like structures in culture as they would in the original organ. When tumor cells were placed on top of these blood vessel-like structures, the in vivo observations of the researchers were reproduced.
With their organotypic models, the researchers discovered that the protein thrombospondin-1, which is prevalent in stable microvasculature, creates a dormant niche by suppressing the growth of breast cancer cells. However, when the tips of these blood cells begin to sprout, the thrombospondin-1 proteins give way to TGF-beta 1 and periostin proteins in the neovasculature, turning it into a metastatic niche that not only permits but also accelerates growth of breast cancer cells.
“The culprit is one that was not necessarily suspected – the microvascular endothelium – and we show that stable or mature microvascular endothelium promotes tumor dormancy,” Ghajar says. “We also show that once the stability of microvascular endothelium is disrupted, e.g. via neoangiogenic sprouting, the dormant niche is disrupted as well. Not only are suppressive factors lost, but sprouting endothelial tips deposit pro-tumor factors that spark micrometastatic outgrowth.”
Identification of dormant niches in basement membrane microvasculature and how those niches become metastatic in neovasculature hold important implications for future breast cancer therapies, Ghajar says. In addition, the organotypic models, “the first to our knowledge to naturally steer fully malignant, genotypically aberrant tumor cells into a quiescent state,” hold promise for future therapy research
“They should prove to be a wonderful tool to screen for therapies that impact tumor dormancy and allow us also to solve many more of the biological mysteries that underlie dormancy,” Ghajar says. “By understanding what controls tumor dormancy, and using these controls to our advantage, we could eventually develop a means to turn cancer into a manageable disease like Type 1 diabetes.”
“This is not a cure, but it is a way to live with the disease and either keep the time bombs [from blowing up] or eliminate the time bombs altogether,” he says.