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Encyclopedia of Cancer, 2015
Scirrhous; Stroma; Stromal cell response
Desmoplasia is the formation of fibrous connective tissue by proliferation of fibroblasts. Desmoplasia is a key component of solid tumor stroma (Fig. 1).
Tumors have many parallels to wounds, including similar inflammatory and desmoplastic responses, and fibroblasts are the key cellular component in the development of desmoplasia. Fibroblasts are recruited into the wound or tumor, secrete and remodel extracellular matrix (ECM) (extracellular matrix remodeling), and serve as scaffolding for other cell types in connective tissue. As fibroblasts incorporate into a tumor environment, they undergo a phenotypic change and acquire an “activated fibroblast” appearance, which are also known as myofibroblasts or tumor-associated fibroblasts. Myofibroblasts have similar markers to fibroblasts, but myofibroblasts upregulate proteins such as α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP-1), and fibronectin fibrils. During wound repair, the number of myofibroblasts returns to a normal level upon wound resolution. In contrast to wound repair, tumor microenvironments simulate a chronic wound in many ways. Thus, local fibroblasts and those that were recruited into the expanding stroma are continuously exposed to activation signals. Activated fibroblasts expand and contribute to an increased stromal response known as desmoplasia. Desmoplasia can be associated with increased tumor stage and poor prognosis in breast cancer patients, but it is unclear whether fibroblasts are active inducers or passive participants in cancer progression. It is clear, however, that activated fibroblasts play a large role in the expanding tumor stroma (stromagenesis).
Fibroblastic stromal cells and desmoplasia have been linked to several activities that promote cancer growth and metastasis (semaphorins) including angiogenesis, epithelial to mesenchymal tran- sition (EMT), and progressive genetic instability. Additionally, fibroblastic stromal cells can dysregulate antitumor immune responses, as exemplified by experiments demonstrating that allogeneic murine tumor cells, when co-injected with fibroblastic stromal cells, can engraft across immunologic barriers. Together, these studies suggest that tissue-specific fibroblasts are influential players in progression of metastatic cancer. However, with the exception of promoting epithelial to mesenchymal transition, the direct biological impact on cancer cells themselves has been difficult to distinguish from indirect mechanisms such as enhanced support for angiogenesis or recruitment of inflammatory cells.
The origins of desmoplastic fibroblasts are not fully understood. Some studies have suggested that stromal cell fibroblasts are recruited to the expanding tumor mass from local tissue fibroblasts. However, other experimental evidences support that additional tumor-associated fibroblasts can be recruited from peripheral fibroblast pools, such as bone marrow-derived mesenchymal stem cells (MSC) or fibrocytes. It has been shown that once fibroblasts are recruited into the expanding stroma, they change their phenotype and may also undergo selective genetic alterations, which may drive additional tumor growth. Desmoplastic tumor fibroblasts have also been shown to carry unique genetic lesions when compared to those found in expanding tumor cells. These observations offer an additional insight into potential mechanisms for how genetic lesions can induce tumor cell expansion.
Fig. 1. Hematoxylin and eosin (H&E) stain. Tumor fibroblasts (i.e., desmoplasia) appear pink
The mechanism for recruitment of desmoplastic fibroblasts into a developing tumor remains poorly defined. Yet several groups have shown that platelet-derived growth factor (PDGF) can contribute to the formation of desmoplasia. In a xenograft model using the human breast carcinoma cell line MCF-7 expressing the cellular oncogene, c-ras, investigators demonstrated that blocking tumor PDGF inhibited the formation of desmoplasia. Others have shown that blocking TGF-a, TGF-b, IGF-I, and IGF-II had no effect on the desmoplastic response. Since these models used murine xenografts, it remains unclear whether PDGF is as critical for the development of desmoplasia in human carcinomas (epithelial tumorigenesis).
One important way that desmoplastic fibroblasts can contribute to tumor growth and metastasis is through the production of multiple growth factors (fibroblast growth factors). Paracrine growth factors such as the stroma-derived factor 1 (SDF-1/CXCL12) (angiogenesis), vascular endothelial growth factor (VEGF) (angiogenesis), fibroblast growth factor (FGF) family, hepatocyte growth factor (HGF), transforming growth factor β (TGF-β) family, interleukin-6 (IL-6), and epidermal growth factor (EGF) have all been linked to increased tumor growth. Desmoplastic fibroblasts also contribute to tumor stroma through the production of fibrous connective tissues and extracellular matrix proteins (fibronectin) (focal adhesion kinase (FAK)). Collagen production is a hallmark feature of desmoplasia. As fibroblasts convert to myofibroblasts or tumor-associated fibroblasts, parallel increases in production of collagen are observed. A pathologist can readily visualize increased levels of tumor collagen using standard histology procedures (pathology), and collagen types I and IV are the most prevalent forms of collagen found within most desmoplastic reactions. Collagen bundles interact with extracellular matrix and cell surface proteins such as integrins (cell adhesion molecules) (focal adhesion kinase (FAK)) to influence the stiffness of a given tumor microenvironment.
Desmoplasia varies extensively between tumors and even within the same tumor. Some studies have suggested that desmoplasia is a defensive mechanism used to wall off the expanding tumor, but other data demonstrate that desmoplasia is associated with increased tumor growth, invasion, and metastasis. It is unclear, however, which underlying mechanisms determine the extent to which desmoplasia may promote tumor progression. As investigators continue to recognize the importance of the tumor microenvironment (Fig. 2), more detailed studies will allow clarification of the biological impact of desmoplasia in tumor development, survival, and metastasis.
Fig. 2. The tumor microenvironment is composed of many cell types that support tumor cell growth and survival
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