StemCell Therapy

Immune Cells Gone Wrong

In a talk provocatively titled MacrophagesEvildoers in Cancer, Jeffrey W. Pollard, Ph.D., of the MRC Centre for Reproductive Health at the University of Edinburgh, described how tumor evolution to malignancy requires manipulation of its tissue microenvironment. This is particularly true, he noted, for the immune infiltrate that is biased away from responding to the tumor to effect control and instead actively promotes progression.

The tumor immune response thus downregulates cytotoxic T-cell responses and promotes tissue repair and morphogenic activities of the infiltrating immune cells, Dr. Pollard indicated in his abstract. Thus, the environment tends to be dominated by innate immune cells, particularly macrophages and neutrophils, while cytotoxic T cells are often excluded.

Dr. Pollards group has been interested in macrophages. In many different mouse models of cancer, these immune cells have been shown to promote tumor progression and enhance metastasis. In fact, he emphasized, macrophages appear to be involved in every step of tumor progression. They stimulate tumor initiation, enhance angiogenesis, promote tumor cell migration and intravasation, increase stem cell viability, suppress immune responses, and, at the metastatic site, promote extravasation and persistent growth.

Macrophage ablation, Dr. Pollards team has observed, results in inhibition of tumor progression and metastasis. It has also found that macrophage biologic activities are induced through a dynamic interplay with tumor cells that often involves reciprocal signaling.

Dr. Pollards group has been particularly interested in the involvement of macrophages in enhancing metastasis, since it is metastatic disease that is responsible for most cancer deaths. The group, stated Dr. Pollard, has demonstrated a chemokine-signaling cascade that results in the recruitment of the progenitor monocytes and their retention in the tissue. This results, he continued, in differentiation of what we have termed metastasis-associated macrophages (MAMs).

MAMs confer survival signals and growth advantage to metastatic cells, elaborated Dr. Pollard. The MAMs, in turn, respond to local signals to upregulate an inflammatory gene signature through the tyrosine kinase transmembrane receptors, vascular endothelial growth factor receptor 1 (VEGFR1 or FLT1) and colony stimulating factor 1 receptor (CSF1R). Furthermore, monocytes appear to be preadapted by the primary tumor to promote metastasis by the generation of preferred sites known as premetastatic niches. Thus, understanding monocyte biology, the mechanisms of their recruitment, and differentiation is of central importance to the fundamental appreciation of the role of macrophages in the tumor.

Read more here:
Solid Advances in Tumor Microenvironment Research - Genetic Engineering & Biotechnology News

This entry was posted on April 10, 2017 at 7:43 pm and is filed under Death by Stem Cells. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |