Cytokine Signaling Network Increases Cancer Stem Cell Population

Mesenchymal stem cells (MSCs) originating in the bone marrow are attracted to the site of breast tumor growth where they stimulate the formation of a growth enhancing environmental niche by secreting molecular signals that mediate tumor invasion and metastasis.

Investigators at the University of Michigan (Ann Arbor, USA) used in vitro systems and mouse models to examine the interaction between bone marrow–derived MSCs and breast cancer stem cells (CSCs).

Cancer stem cells are highly resistant to current chemotherapies and radiation treatment, which is one reason that cancer frequently returns after treatment. In previous studies, it was found that breast cancers in mice sent out signals that attracted MSCs from bone marrow into the area of the tumor where these cells interacted and stimulated the growth of breast CSCs.

In the current study published in the January 15, 2011, issue of the journal Cancer Research, a population of labeled MSCs was introduced into the tibia of NOD/SCID mice. These cells traveled to sites of growing breast tumor xenografts where they accelerated tumor growth by increasing the breast CSC population. With immunochemistry, MSC–CSC niches were identified in these tumor xenografts as well as in frozen sections from primary human breast cancers. Bone marrow–derived MSCs may accelerate human breast tumor growth by generating cytokine networks that regulate the CSC population.

The molecule signals comprising the cytokine networks have now been identified. In the current paper the investigators reported that interaction between the stem cell types was mediated by a cytokine network involving CXCL7 (chemokine (C-X-C motif ligand 7) and IL6 (Interleukin-6).

CXCL7 is a protein that is released in large amounts from platelets following their activation. It stimulates various processes including mitogenesis, synthesis of extracellular matrix, glucose metabolism, and synthesis of plasminogen activator. IL-6 is a cytokine derived from activated T lymphocytes that has many functions, including induction of B-cell growth; induction of B-cell differentiation and antibody production; induction of differentiation and proliferation of T cells; synergistic induction with IL-3 of hematopoietic cell growth; and induction of hepatocyte secretion of acute-phase inflammatory proteins.

"The importance of this is that we may be able to attack breast cancer stem cells indirectly by blocking these signals from the niche,” said senior author Dr. Max S. Wicha, professor of oncology at the University of Michigan.

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