Hypoxic Cancer Cells Release Signaling Molecules That Promote Tumor Tolerance

Cancer cells growing under conditions of hypoxia have been found to release diverse chemical messengers, some of which stimulate angiogenesis and some of which induce immune system tolerance by promoting the recruitment of regulatory T (Treg) cells.

Investigators at the University of Pennsylvania (Philadelphia, USA) worked with cultures of ovarian tumor cells growing either under hypoxic conditions or under conditions of normal oxygen. Since it was known that under hypoxic conditions tumor cells release proangiogenic signals that are tumor suppressors, the investigators were searching for other molecules that would promote tumor survival and growth.

They reported in the July 13, 2011, online edition of the journal Nature that tumor hypoxia promoted the recruitment of regulatory T (Treg) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promoted tumor tolerance and angiogenesis.

“For the first time, we are realizing that the two programs – angiogenesis and immune suppression – are coregulated and the two programs are mediated by the same cell types,” said senior author Dr. George Coukos, professor of reproductive biology at the University of Pennsylvania. “This creates new therapeutic opportunities, since the study reveals that in order to effectively suppress angiogenesis; one should also suppress a type of immune cell, called regulatory T cells. Thus, commonly used antiangiogenesis therapies should be combined with therapeutic maneuvers that eliminate regulatory T cells.”

“The tools to eliminate T-regs effectively are not presently available in the clinic, but the field is definitely advancing, with several candidate strategies currently being tested,” said Dr. Coukos. “The other implication of this study is that if antiangiogenesis therapy induces tumor hypoxia that could create a rebound increase in regulatory T cells. That rebound could account for some of the resistance that is commonly seen in the clinic after antiangiogenesis therapy is instituted.”

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