1-Cancer microenvironment: the role of stroma in neoplasia (more USCAP 2010)
Posted May 06 2010 8:27pm
This post is more from USCAP 2010. I attended the "Advanced Molecular BIology" Special Course at USCAP on March 23. One of the highlights was Dr. Rob West's presentation, "The Role of Stroma in Neoplasia." I also had the pleasure of sharing a van ride with him to Dulles where we had a chance (because of miserable traffic) to talk for a long while about the cancer microenvironment, cancer stem cells, and, of course, our children. What follows is my summary of his talk.
The role of the stroma in cancer can be summarized by two broad concepts:
What are the components of the cancer microenvironment?
Endothelial cells (and bone marrow derived mesenchymal stem cells?)
Leukocytes, especially macrophages
Myofibroblasts are key players in the cancer microenvironment because they modulate the extracellular matrix "landscape," regulate angiogenesis, and secrete growth factors and cytokines that influence a wide variety of cellular functions of cancer cells.
If the tumor is going to grow, the nascent tumor and surrounding stroma must recruit endothelial cells by expressing angiogenic factors (e.g. VEGF) which tips the balance of pro-angiogenic factors over anti-angiogenic factors. Hypoxia, p53 mutation, decreased thrombospondin-1, increased HIF are other factors that promote angiogenesis and the angiogenic switch." Furthermore, there appears to be an "endothelial-to-mesenchymal transition" (EnMT) that involves the development of vascular networks around the tumor composed of "tip cells"--vessel sprouts without vascular lumens. This process is reminiscent of EnMT that occurs in tissue patterning during embryogenesis and is important for stabilizing the fragile neovasculature at the interface of the tumor and microenvironment.
The extracellular matrix is not a passive scaffold but is recognized now as an active, evolving compartment. Invasion into the ECM by cancer cells is a multi-step process that involves dissociation and detachment from surrounding cancer cells, attachment to surrounding ECM, degradation of ECM, and migration through the remodeled ECM. The other cellular components critically influence this entire process.
Macrophages are now recognized as pivotal in promoting tumor cell migration and invasion, angiogenesis, remodeling of the ECM, and the "metastatic niche." In particular, macrophage subsets are being defined as "tumor-associated macrophages."