Groundbreaking work by Hendrix and colleagues is elucidating how, by becoming more like unspecialized stem cells, aggressive melanoma cells gain enhanced abilities to migrate, invade and metastasize while remaining virtually undetected by the immune system.
Hendrix and co-researchers previously demonstrated that a three-dimensional matrix conditioned by hESCs induced metastatic melanoma cells to revert to a normal, skin cell-like type with the ability to form colonies in the manner of hESCs (Postovit and Seftor et al, Stem Cells 24:501-505, 2006).
"This observation allowed us to appreciate the powerful influence of the hESC microenvironment on the reprogramming of metastatic melanoma cells," Hendrix said.
In subsequent experiments, Hendrix, Postovit and co-researchers found that aggressive melanoma and breast cancer produce a "morphogenic" protein called Nodal, which is essential for human embryonic stem cell pluripotency (Topczewska et al, Nature Medicine 12:925-932, 2006). Other researchers have found that Nodal also is present in testicular cancer.
"Thus, Nodal may serve as a prognostic marker of aggressive behaviors in human cancers," Hendrix said.
As described in the PNAS study, the Lefty protein inhibits production of Nodal and therefore plays a major role in embryonic cell differentiation and development - under normal circumstances.
Hendrix and colleagues discovered that metastatic tumor cells do not express Lefty, allowing them to overproduce Nodal in an unregulated manner.
However, when the group exposed metastatic tumor cells to the microenvironment of hESCs containing Lefty, they witnessed dramatically reduced Nodal expression (production) in these cancer cells together with decreased tumor cell growth and invasiveness and an increase in apoptosis, or programmed cell suicide.
Although exposure to a hESC microenvironment inhibited N
|SOURCE Northwestern University|
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