High grade dysplasia (carcinoma in situ) in the uterine cervix [3] |
The order of events during inflammation and repair become disorganized during carcinogenesis. Tumors can be viewed as 'wounds that do not heal', and granulocytes, macrophages, endothelial cells, and fibroblasts - cells involved with acute inflammation - react in a way to promote the survival and replication of cancer cells. [1] Recent data indicates that stromal and inflammatory cells are involved in directing formation of blood vessels to a tumor. [1]
- Cancer cells
- Non-cancer cells
- Secreted soluble factors
- Non-cellular solid material, including the extra-cellular matrix
The Role of Surrounding Cells in Cancer Development Fibroblasts Definition
NIH/3T3 Fibroblasts in cell culture [7] |
Typical Role of CellsFibroblasts help in the healing of wounds by invading lesions, generating extra cellular matrix and facilitating contractions of healing wounds. [4]
Role in Cancer DevelopmentData indicates that fibroblasts are involved in defining the rate and extent of cancer progression. [4] Reactive stroma provides oncogenic signals facilitating tumorigenesis, and there are increased numbers of fibroblasts in reactive stroma. The overall effect, though, of altered ECM secreted and organized by fibroblasts is not understood well.
Tumor Angiogenesis
Vascular endothelial growth factor helps through the extravasation of fibrin to attract fibroblasts to the site of tumors, and the attracted cells, including fibroblasts, inflammatory cells, and endothelial cells, produce ECM rich in fibronectin and type I collagen, which is conducive to initiating tumor angiogenesis. [4]
Metastasis
Fibroblasts are a source of ECM-degrading proteases, including MMPs, which may allow cancer cells to cross boundaries of tissue and escape, MMPs also affect the motility and invasiveness of cancer cells.
Studies also indicate that activated fibroblasts at the site of metastases promote the proliferation of cancer cells. [4]
A blood smear showing a neutrophil granulocyte; the three-lobulated nucleus can be seen. [8] |
Neutrophils are able to both promote tumor elimination or increase the growth of tumor cells.
Cascade of FactorsThe neutrophil-dependent release of vascular endothelial growth factor A is associated with an angiogenic factor made in tumors. Endothelial cell invasion and vessel formation ultimately result from a cascade of events. Chemokines that act on the CXCR2 receptor recruit neutrophils and then vascular endothelial growth factor and matrix metalloproteinase 9. [1]
A macrophage of a mouse stretching its "arms" (Pseudopodia) to engulf two particles, possibly pathogens [9] |
Macrophages DefinitionMacrophages are white blood cells that phagocytose (engulf and digest) debris of cells and pathogens. They stimulate lymphocytes and immune cells to act against the pathogen. [9]
Change of PhenotypeThe phenotype of tumor-associated macrophages (M2) may be very different from normal macrophages (M1). There may be additional types of macrophages based on the microenvironment. [1]
Influence on Tumor CellsM2 macrophages may influence tumor cells directly and promote aggressiveness. They may help to free prostrate cancer cells from androgen dependence, which is a step in the progression of malignancy.
Histological section through testicular parenchyma of a boar. 1 Lumen of Tubulus seminiferus contortus, 2 spermatids, 3 spermatocytes, 4 spermatogonia, 5 Sertoli cell, 6 Myofibroblasts, 7 Leydig cells, 8 capillaries [10] |
Myofibroblast DefinitionA myofibroblast is a type of cell that is between a fibroblast and a smooth muscle cell in differentiation. These cells serve different roles in various organs, produce several growth factors, cytokines, chemokines, and ECM components, and express many receptors. They are a source and target of soluble mediators. [1]
Role in Tumor DevelopmentMyofibroblasts may increase tumour growth and expansion once invasion of tissue is initiated, and they are activated when tissue integrity is compromised.
Adipocytes
DefinitionAdipocytes are the type of cells that primarily constitute adipose tissue, which secretes several specific cytokines (the adipokines leptin, adiponectin, resistin and visfatin), and a specialty of adipocytes is storing energy as fat.
Role in Cancer DevelopmentAdipose tissue secretes metalloproteinases, which influence inflammation and angiogenesis.
Communication between a Tumor and its SurroundingsHomeostasis in healthy tissue is achieved by a balance of cell proliferation and death maintained by intercellular communication. [5] Communication between a tumor and the surroundings includes pro- and anti-tumor interactions.
Transforming Growth Factor β (TGF-β)
Influence of TGF-βTransforming growth factor β is a molecule that is a regulator of tumor progression. Secreted by cells within the tumor microenvironment, TGF-β powerfully inhibits cell growth, yet mutations in advanced carcinomas enable the cells to grow even in the presence of TGF-β. Rather than being inhibited by this molecule, tumors can utilize it to reduce the growth of neighboring normal cells. [6]
Conditions within the Tumor Microenvironment Massive Cell DeathCell death within the tumor microenvironment results in release of proteins and additional molecules.
HypoxiaHypoxia refers to low oxygen levels, and it results in generation of oxygen free radicals, leading to DNA damage, which is less efficient in a hypoxic environment. Damage of DNA increases the mutation rate, causing greater variation in the tumor population. Also, cells most fit to survive do in the harsh environment and continue to grow.
Low pHThere are acidic conditions within the tumor microenvironment.
Low Glucose Levels Abnormal Properties of Surrounding CellsThe normal cells that surround the tumor may develop mutations and is often disorganized. Two sources of the abnormalities could be (1) hypoxia and low pH of the tumor microenvironment that could induce mutations and (2) the soluble products, such as growth factors and cytokines, that are released from the tumor, which may affect gene expression of stromal cells. [6]
- Nature Reviews Cancer 7, (February 2007)
- "Dictionary of Cancer Terms" National Cancer Institute http://www.cancer.gov/templates/db_alpha.aspx?CdrID=561725 (Accessed March 17, 2009)
- "Carcinoma in situ" Wikipedia http://en.wikipedia.org/wiki/Carcinoma_in_situ (Accessed March 16, 2009)
- Nature Reviews Cancer 6, 392-401 (May 2006)
- Nature Reviews Cancer, advance online publication, Published online 12 March 2008 | doi:10.1038/nrc2618
- "Cancer Quest" Emory University http://www.cancerquest.org/index.cfm?page=4763 (Accessed March 17, 2009)
- "Fibroblasts" Wikipedia http://en.wikipedia.org/wiki/Fibroblasts (Accessed March 16, 2009)
- "Neutrophil Granulocyte" Wikipedia http://en.wikipedia.org/wiki/Neutrophil_granulocyte (Accessed March 17, 2009)
- "Macrophage" Wikipedia http://en.wikipedia.org/wiki/Macrophage (Accessed March 17, 2009)
- "Myofibroblast" WIkipedia http://en.wikipedia.org/wiki/Myofibroblast (Accessed March 17, 2009)