CAFs and MSCs in the Tumor Microenvironment
Understanding the role of
cancer-associated stromal myofibroblasts (CAFs) in tumor progression has
become
a major research emphasis in our lab. The presence in carcinomas of
large
numbers of myofibroblasts originally suggested the concept of cancer as a
non-healing wound, and a number of observations have
now implicated these cells as contributing to cancer growth, invasion
and
metastasis. Tumors consist of many cell types, including cancer cells
and
diverse stromal cells that constitute the tumor microenvironment and
contribute
to tumor progression. The stromal microenvironment of tumors includes a
mixture
of hematopoietic and mesenchymal cells, the latter of which is comprised
mostly
by cancer-associated fibroblasts (CAFs), a cell type that closely
resembles
normal myofibroblasts (MF) present in the gastrointestinal mucosa.
However, functionally, CAFs behave quite differently from MF, and
clinical evidence supports the notion that stroma cells contribute in
important
ways to the development of a wide variety of malignant tumors. Tumors
that have a
desmoplastic stroma, consisting of more stromal cells disrupting the
tissue
homogeneity, often have a poorer prognosis.
Cancer-associated fibroblasts (CAFs) are usually considered to be activated fibroblasts that express aSMA. In normal gastrointestinal stroma, fibroblasts are usually quiescent and characterized by expression of vimentin and collagen but not aSMA, while CAFs usually express aSMA, vimentin, and FSP1, and appear to be activated and highly proliferative. Since CAFs have altered biology compared to normal MFs and seem to accumulate in tumors, a number of studies have explored their origins. Sources that have been considered include resident fibroblasts, smooth muscle cells, endothelial cells, epithelial cells (through EMT), fibrocytes and recruited BM-derived cells (BMDC) such as MSCs. MSCs are defined as multipotent stem cells that contribute to normal bone, adipose, cartilage and muscle. MSCs originate in the BM but can be found throughout the body; they are often involved in tissue remodeling after injury or chronic inflammation. MSCs are among the BM-derived cells that have been shown to be recruited to tumors and to promote their growth. Interestingly, they appear to be relatively easy to culture when grown in low serum media on plastic dishes. Previous studies have suggested that MSCs can be induced to differentiate into CAFs, particularly when exposed to tumor-conditioned media.
We recently demonstrated that a significant percentage of CAFs in inflammation-associated gastric cancer originate from MSCs and that MFs contribute to the normal stem cell niche in the BM. MSC give rise to their own niche cells, which might apply to other stem cell niches. In inflammation-induced cancer progression MFs increases in the BM niche and blood during progression to dysplasia. Therefore, we propose a model in which the earliest stages of tumor development are characterized by remodeling of the BM, followed by relocation of the MSC-CAF stem cell niche to the tumor site where it promotes tumor progression.
Cancer-associated fibroblasts (CAFs) are usually considered to be activated fibroblasts that express aSMA. In normal gastrointestinal stroma, fibroblasts are usually quiescent and characterized by expression of vimentin and collagen but not aSMA, while CAFs usually express aSMA, vimentin, and FSP1, and appear to be activated and highly proliferative. Since CAFs have altered biology compared to normal MFs and seem to accumulate in tumors, a number of studies have explored their origins. Sources that have been considered include resident fibroblasts, smooth muscle cells, endothelial cells, epithelial cells (through EMT), fibrocytes and recruited BM-derived cells (BMDC) such as MSCs. MSCs are defined as multipotent stem cells that contribute to normal bone, adipose, cartilage and muscle. MSCs originate in the BM but can be found throughout the body; they are often involved in tissue remodeling after injury or chronic inflammation. MSCs are among the BM-derived cells that have been shown to be recruited to tumors and to promote their growth. Interestingly, they appear to be relatively easy to culture when grown in low serum media on plastic dishes. Previous studies have suggested that MSCs can be induced to differentiate into CAFs, particularly when exposed to tumor-conditioned media.
We recently demonstrated that a significant percentage of CAFs in inflammation-associated gastric cancer originate from MSCs and that MFs contribute to the normal stem cell niche in the BM. MSC give rise to their own niche cells, which might apply to other stem cell niches. In inflammation-induced cancer progression MFs increases in the BM niche and blood during progression to dysplasia. Therefore, we propose a model in which the earliest stages of tumor development are characterized by remodeling of the BM, followed by relocation of the MSC-CAF stem cell niche to the tumor site where it promotes tumor progression.
