Cancer-associated fibroblast
A cancer-associated fibroblast is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.
CAFs have been found to be abundant in a tumour stroma.Myofibroblasts and fibroblasts make up CAFs.
The functions of these CAFs have been known to stimulate angiogenesis, supporting the formation of tumours and thus proliferation of cancer cell and metastasis. Cancer cells are usually also drug resistant, which is contributed by CAFs. As such, this interaction is being studied for potential anti-cancer therapy.
Normal fibroblasts aid in the production of components of the extracellular matrix such as collagens, fibres, glycosaminoglycans and glycoproteins and are therefore vital in tissue repair in wound healing.
CAFs however, are derived from either normal fibroblasts, pericytes, smooth muscle cells, fibrocytes or mesenchymal stem cells These CAFs then go on to support tumour growth by secreting growth factors such as Vascular Endothelial Growth Factor, Platelet Derived Growth Factor and Fibroblast Growth Factor and other chemokines to stimulate angiogenesis and thus the growth of a tumour.
Markers
CAFs produce a number of proteins that are specific to the origin of the cells. However, as there are no specific protein to CAFs, a combination of these proteins are then used as markers to identify CAFs High levels of the marker would mean a low prognosis due to the stage of cancer.| Name of markers | Functions |
| α-smooth muscle actin | Marker for myofibroblasts |
| Fibroblast activation protein | Marker for myofibroblasts |
| Tenascin-C | Regulates adhesion of cancer cells for invasion |
| Periostin | Product of process of tissue repair |
| Neuron glial antigen-2 | More associated with pericytes. What fibroblasts come from |
| Vimentin | Plasma membrane associated protein |
| Desmin | Marker for maturation of microvessels |
| Platelet derived growth factor receptor-α and β | |
| Fibroblast specific protein-1 - S100A4 | Myofibroblasts and fibroblasts make up CAFs |
| ASPN | potential new marker of CAF |
| STC1 | Potential new marker of CAF |
Markers for CAFs are notably similar to those of surrounding tumour-associated cells but at the same time, display massive heterogeneity of behaviour, appearance and genotype.
In 2017 Swedish researchers tried to classify molecularly distinct fibroblasts into groups depending on their differential expression of markers. They found overlapping expression patterns which supported the idea that there are transitional states and even identified pluripotency in some patients’ activated fibroblasts.
Pleotropic functions require cell plasticity.
While there are positive markers for CAFs, there are also negative markers namely; cytokeratin and CD3, as CAFS do not have epithelial and endothelial characteristics.
Potential Origin
The origins of CAF differ depending on the tumour histotype and where the tumour originated in the first place but can be broadly separated into 4 categories. The origin of each type of CAF has a role in determining the function of that specific cell.Resident
These CAFs arise from fibroblasts within the vicinity of the tumour that have been recruited by cancer derived growth factor. This process is similar to active inflammation with the main difference between these two processes being that, in cancer, the fibroblasts can’t be deactivated which has led to tumours being referred to as “wounds that do not heal.” It is believed that most CAFs arise from differentiated resident fibroblast cells.The normal fibroblast cells receive a hormone signal from nearby cells, indicating that it must become activated, and is thus classed as a CAF. It is unclear why normal fibroblasts transition into CAFs but it has been found that by adding transforming growth factor- Beta to fibroblasts in culture they start to display features of CAFs. TGF- beta is known to control the activation of fibroblasts in inflammation.
Recruitment from Other Sites
CAFs can also be recruited from a remote source, such as the bone marrow.Differentiation
CAFs can also be derived from differentiation of other cell types such as MSCs. Another suggested origin is differentiation of endothelial or epithelial cells via trans-differentiation or epithelial to mesenchymal transition, respectively.It has been suggested that CAFs are better conceptualised as a “cell state” Research has found that CAF trans-differentiation can be caused by epigenetic factors.
Roles in Cancer
Prognosis
In general, the presence and density of cancer associated fibroblasts point towards a bad prognosis for the patient, and so, are pro-tumour. These could however be used as markers for diagnosis and therapies, thus diagnosing at an earlier stage.The presence of podoplanin in CAFs has been found to play a fundamental role in worsening the prognosis of patients with lung adenocarcinoma; this could however be helpful as a marker to diagnose at an early stage.
In oesophageal adenocarcinomas, CAFs release the ECM protein periostin and promote tumour cell growth through paracrine signalling. However, blocking specific integrin receptors and pathways can ceases the invasion of tumor cells. The greater the density of CAFs found in oral cancer, the poorer the prognosis, as this significantly decreases the 5 year survival rate. Being female in this study also proved to be a bigger risk factor, with men being protected more against the effects.
Effect on Tumour Cells
Cancer-associated fibroblasts have been found to promote tumour growth. They do this through a number of different mechanisms, notably angiogenesis, metastasis and immune evasion. CAF express various cytokines and factors, which activate and contribute to pathways favouring tumorigenesis. They may disrupt normal cell functions, such as cell cycle regulation and cell death, or signal to specific types of cells to mobilize and activate their pro-tumour actions. Furthermore, it has been found that the effect of CAF on neoplastic cells is unique to the type of tumour cells.Cytokine release from CAFs have been linked to breast carcinomas through the metabolism and production of androgen synthesis enzymes.
Furthermore on the topic of the progression of breast cancer, CAFs induces the release growth factors such as FGF and HGF which in turn induces the hyperproliferation of epithelial cells of the breast. EMT and ECM reorganisation are further mechanisms by which the CAFs induce cancer. FSP1, which is secreted by CAFs, promotes tumours through another method - by altering the tumour microenvironment. Some CAFs also recycle the by-products of anaerobic metabolism by resorting to other metabolic pathways to sustain the growth of cancer cells.