Cancer-associated fibroblast
CAFs are a complex and abundant cell type within the tumour microenvironment;[1] the number cannot decrease, as they are unable to undergo apoptosis.
[5] The functions of these CAFs have been known to stimulate angiogenesis, supporting the formation of tumours and thus proliferation of cancer cell and metastasis.
[8] 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.
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.
[19] 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 (suggesting progenitor cells).
[31] In general, the presence and density of cancer associated fibroblasts (CAF) point towards a bad prognosis for the patient, and so, are pro-tumour.
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.
[32] In oesophageal adenocarcinomas, CAFs release the ECM (Extracellular Matrix) protein periostin and promote tumour cell growth through paracrine signalling.
[33] The greater the density of CAFs found in oral cancer, the poorer the prognosis, as this significantly decreases the 5 year survival rate.
[35] In turn, this promotes the cancer process through tumour growth and also fosters angiogenesis, metastasis and immune evasion.
Cytokine release from CAFs have been linked to breast carcinomas through the metabolism and production of androgen synthesis enzymes.
[41][42] CAFs can produce cytokine TGF-β which has inhibitory effect on T cells, macrophages and neutrophils thus they are not able to promote immune response against the tumor.
[30] Other mechanism how T cells are suppressed by CAFs is high expression of checkpoint molecules such as PD-L1, PD-L2, B7-H3/H4, galactins and the enzyme IDO.
[44] Additionally, CAF have the ability to break down proteins in the extracellular matrix and basement membranes leading to disruption to the normal structure allowing cells to move away from their primary region.
For instance, this can either be done by an increased secretion of antiapoptotic factors or by altering the cell environment (e.g. pH) to counteract the actions of the drug.
