Cancer-associated fibroblast

CAFs produce a number of proteins that are specific to the origin of the cells.{{cite journal | vauthors = Augsten M | title = Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment | journal = Frontiers in Oncology | volume = 4 | pages = 62 | date = 2014 | pmid = 24734219 | pmc = 3973916 | doi = 10.3389/fonc.2014.00062 | doi-access = free }} 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.

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.{{Cite book|title=Tissue Repair, Contraction and the Myofibroblast| vauthors = Baglole CJ, Smith TJ, Foster D, Sime PJ, Feldon S, Phipps RP | chapter = Functional Assessment of Fibroblast Heterogeneity by the Cell-Surface Glycoprotein Thy-1 |date=2006|publisher=Springer, Boston, MA|isbn=9780387336497|series=Biotechnology Intelligence Unit|pages=32–39|language=en|doi=10.1007/0-387-33650-8_4}}

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).

Pleotropic functions (e.g. tumour-promoting and tumour-inhibiting) require cell plasticity.{{cite journal | vauthors = Busch S, Andersson D, Bom E, Walsh C, Ståhlberg A, Landberg G | title = Cellular organization and molecular differentiation model of breast cancer-associated fibroblasts | journal = Molecular Cancer | volume = 16 | issue = 1 | pages = 73 | date = April 2017 | pmid = 28372546 | pmc = 5376683 | doi = 10.1186/s12943-017-0642-7 | doi-access = free }}

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.{{cite journal | vauthors = Sukowati CH, Anfuso B, Crocé LS, Tiribelli C | title = The role of multipotent cancer associated fibroblasts in hepatocarcinogenesis | journal = BMC Cancer | volume = 15 | pages = 188 | date = March 2015 | pmid = 25879842 | pmc = 4389787 | doi = 10.1186/s12885-015-1196-y | author4-link = Claudio Tiribelli | doi-access = free }}

File:Cancer-associated Fibroblasts.png

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.{{cite journal | vauthors = Nair N, Calle AS, Zahra MH, Prieto-Vila M, Oo AK, Hurley L, Vaidyanath A, Seno A, Masuda J, Iwasaki Y, Tanaka H, Kasai T, Seno M | display-authors = 6 | title = A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 6838 | date = July 2017 | pmid = 28754894 | pmc = 5533745 | doi = 10.1038/s41598-017-07144-5 | bibcode = 2017NatSR...7.6838N }}

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.”{{cite journal | vauthors = Dvorak HF | title = Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing | journal = The New England Journal of Medicine | volume = 315 | issue = 26 | pages = 1650–1659 | date = December 1986 | pmid = 3537791 | doi = 10.1056/nejm198612253152606 }} It is believed that most CAFs arise from differentiated resident fibroblast cells.{{cite journal | vauthors = Wang J, Min A, Gao S, Tang Z | title = Genetic regulation and potentially therapeutic application of cancer-associated fibroblasts in oral cancer | journal = Journal of Oral Pathology & Medicine | volume = 43 | issue = 5 | pages = 323–334 | date = May 2014 | pmid = 23782231 | doi = 10.1111/jop.12098 | doi-access = free }}

The normal fibroblast cells receive a hormone signal from nearby cancer cells, indicating that it must become activated, and is thus classed as a CAF.{{cite journal | vauthors = De Veirman K, Rao L, De Bruyne E, Menu E, Van Valckenborgh E, Van Riet I, Frassanito MA, Di Marzo L, Vacca A, Vanderkerken K | display-authors = 6 | title = Cancer associated fibroblasts and tumor growth: focus on multiple myeloma | journal = Cancers | volume = 6 | issue = 3 | pages = 1363–1381 | date = June 2014 | pmid = 24978438 | pmc = 4190545 | doi = 10.3390/cancers6031363 | doi-access = free }} It is unclear why normal fibroblasts transition into CAFs but it has been found that by adding transforming growth factor-β to fibroblasts in culture they start to display features of CAFs.{{cite journal | vauthors = Kalluri R, Zeisberg M | title = Fibroblasts in cancer | journal = Nature Reviews. Cancer | volume = 6 | issue = 5 | pages = 392–401 | date = May 2006 | pmid = 16572188 | doi = 10.1038/nrc1877 | s2cid = 20357911 }} TGF-β is known to control the activation of fibroblasts in inflammation.

CAFs can also be recruited from a remote source, such as the bone marrow. For example, fibroblasts recruited from the bone marrow were found in breast cancer.{{cite journal | vauthors = Chen X, Song E | title = Turning foes to friends: targeting cancer-associated fibroblasts | journal = Nature Reviews. Drug Discovery | volume = 18 | issue = 2 | pages = 99–115 | date = February 2019 | pmid = 30470818 | doi = 10.1038/s41573-018-0004-1 | s2cid = 256745216 }}

CAFs can also be derived from differentiation of other cell types such as mesenchymal stem cells, which was proved in murine models with cancers such as glioma, breast, pancreatic and gastric cancers. Another suggested origin is differentiation of endothelial or epithelial cells via trans-differentiation or epithelial to mesenchymal transition, respectively.{{cite journal | vauthors = Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA | display-authors = 6 | title = Mesenchymal stem cells within tumour stroma promote breast cancer metastasis | journal = Nature | volume = 449 | issue = 7162 | pages = 557–563 | date = October 2007 | pmid = 17914389 | doi = 10.1038/nature06188 | s2cid = 4317561 | bibcode = 2007Natur.449..557K }}{{Cite book|title=Biology of stem cells and the molecular basis of the stem state | vauthors = Zipori D |date=2009|publisher=Humana|isbn=978-1-60761-129-5|location=Totowa, N.J.|oclc=432708883}}

Less common origin of CAFs is by differentiation of other tumor adjacent cells such as epithelial or endothelial cells, adipocytes, pericytes and smooth muscle cells. Adipocytes, especially white adipocytes transdifferentiate into CAFs upon activation with TGF-β1. Through TGF-β1 can be transformed also peritoneal mesothelial cells.{{cite journal | vauthors = Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, Zhang B, Meng Q, Yu X, Shi S | display-authors = 6 | title = Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives | journal = Molecular Cancer | volume = 20 | issue = 1 | pages = 131 | date = October 2021 | pmid = 34635121 | doi = 10.1186/s12943-021-01428-1 | pmc = 8504100 | doi-access = free }}

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.{{cite journal | vauthors = Rudnick JA, Kuperwasser C | title = Stromal biomarkers in breast cancer development and progression | journal = Clinical & Experimental Metastasis | volume = 29 | issue = 7 | pages = 663–672 | date = October 2012 | pmid = 22684404 | doi = 10.1007/s10585-012-9499-8 | s2cid = 14507468 }}

In general, the presence and density of cancer associated fibroblasts (CAF) 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.{{cite journal | vauthors = Kubouchi Y, Yurugi Y, Wakahara M, Sakabe T, Haruki T, Nosaka K, Miwa K, Araki K, Taniguchi Y, Shiomi T, Nakamura H, Umekita Y | display-authors = 6 | title = Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma | journal = Histopathology | volume = 72 | issue = 3 | pages = 490–499 | date = February 2018 | pmid = 28881047 | doi = 10.1111/his.13390 | s2cid = 24402475 | url = http://repository.lib.tottori-u.ac.jp/files/public/0/5655/20180622144355962343/G11_15101A00879A.pdf }}

In oesophageal adenocarcinomas, CAFs release the ECM (Extracellular Matrix) protein periostin and promote tumour cell growth through paracrine signalling. However, blocking specific integrin receptors and pathways can ceases the invasion of tumor cells.{{cite journal | vauthors = Underwood TJ, Hayden AL, Derouet M, Garcia E, Noble F, White MJ, Thirdborough S, Mead A, Clemons N, Mellone M, Uzoho C, Primrose JN, Blaydes JP, Thomas GJ | display-authors = 6 | title = Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in oesophageal adenocarcinoma | journal = The Journal of Pathology | volume = 235 | issue = 3 | pages = 466–477 | date = February 2015 | pmid = 25345775 | pmc = 4312957 | doi = 10.1002/path.4467 }} 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.{{Cite journal| vauthors = Vered M, Graizel D, Zlotogorski-Hurvitz A, Rosen E, Tsesis I |journal=Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology |volume=124 |issue=3 |pages=e222 |doi=10.1016/j.oooo.2017.06.080 |year=2017 |title=The Prognostic Significance of Cancer-Associated Fibroblasts in Oral Cancer: A Systematic Review of the Literature and Meta-Analysis }}

Cancer-associated fibroblasts negatively influence the outcome of oncological diseases. These cells create a stromal niche for cancer cells and especially cancer stem cells, where they employ both paracrine and direct cell-contact to maintain stemness in cancer stem cells. In turn, this enables these cancer stem cells to escape chemotherapy and radiotherapy, while the cancer-associated fibroblasts also create an environment that allows cancer cells to escape the action anti-tumour immunity.{{cite journal | vauthors = Liu J, Li P, Wang L, Li M, Ge Z, Noordam L, Lieshout R, Verstegen MM, Ma B, Su J, Yang Q, Zhang R, Zhou G, Carrascosa LC, Sprengers D, IJzermans JN, Smits R, Kwekkeboom J, van der Laan LJ, Peppelenbosch MP, Pan Q, Cao W | display-authors = 6 | title = Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance | journal = Cellular and Molecular Gastroenterology and Hepatology | volume = 11 | issue = 2 | pages = 407–431 | date = 2021 | pmid = 32932015 | pmc = 7788239 | doi = 10.1016/j.jcmgh.2020.09.003 }} In turn, this promotes the cancer process through tumour growth and also fosters angiogenesis, metastasis and immune evasion. CAF express various cytokines and factors, which activate and contribute to pathways favouring tumorigenesis.{{cite journal | vauthors = Gascard P, Tlsty TD | title = Carcinoma-associated fibroblasts: orchestrating the composition of malignancy | journal = Genes & Development | volume = 30 | issue = 9 | pages = 1002–1019 | date = May 2016 | pmid = 27151975 | pmc = 4863733 | doi = 10.1101/gad.279737.116 }} 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.{{cite journal | vauthors = Öhlund D, Elyada E, Tuveson D | title = Fibroblast heterogeneity in the cancer wound | journal = The Journal of Experimental Medicine | volume = 211 | issue = 8 | pages = 1503–1523 | date = July 2014 | pmid = 25071162 | pmc = 4113948 | doi = 10.1084/jem.20140692 }} 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.{{cite journal | vauthors = Kikuchi K, McNamara KM, Miki Y, Moon JY, Choi MH, Omata F, Sakurai M, Onodera Y, Rai Y, Ohi Y, Sagara Y, Miyashita M, Ishida T, Ohuchi N, Sasano H | display-authors = 6 | title = Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor-negative breast carcinoma | journal = Breast Cancer Research and Treatment | volume = 166 | issue = 3 | pages = 709–723 | date = December 2017 | pmid = 28831645 | doi = 10.1007/s10549-017-4464-5 | s2cid = 9157263 }}

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{{clarify|What is EMT?|date=August 2020}} and ECM reorganisation are further mechanisms by which the CAFs induce cancer.{{cite journal | vauthors = Buchsbaum RJ, Oh SY | title = Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to Go | journal = Cancers | volume = 8 | issue = 2 | pages = 19 | date = January 2016 | pmid = 26828520 | pmc = 4773742 | doi = 10.3390/cancers8020019 | doi-access = free }} FSP1, which is secreted by CAFs, promotes tumours through another method - by altering the tumour microenvironment (TME).{{cite journal | vauthors = Xing F, Saidou J, Watabe K | title = Cancer associated fibroblasts (CAFs) in tumor microenvironment | journal = Frontiers in Bioscience | volume = 15 | issue = 1 | pages = 166–179 | date = January 2010 | pmid = 20036813 | pmc = 2905156 | doi = 10.2741/3613 }} Some CAFs also recycle the by-products of anaerobic metabolism by resorting to other metabolic pathways to sustain the growth of cancer cells.{{cite journal | vauthors = Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E | title = Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma | journal = Cancer Research | volume = 66 | issue = 2 | pages = 632–637 | date = January 2006 | pmid = 16423989 | doi = 10.1158/0008-5472.CAN-05-3260 | doi-access = free }}{{cite journal |last1=Cruz-Bermúdez |first1=Alberto |last2=Laza-Briviesca |first2=Raquel |last3=Vicente-Blanco |first3=Ramiro J. |last4=García-Grande |first4=Aránzazu |last5=Coronado |first5=Maria José |last6=Laine-Menéndez |first6=Sara |last7=Alfaro |first7=Cristina |last8=Sanchez |first8=Juan Cristobal |last9=Franco |first9=Fernando |last10=Calvo |first10=Virginia |last11=Romero |first11=Atocha |last12=Martin-Acosta |first12=Paloma |last13=Salas |first13=Clara |last14=Garcia |first14=José Miguel |last15=Provencio |first15=Mariano |title=Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-β signaling |journal=Free Radical Biology and Medicine |date=January 2019 |volume=130 |pages=163–173 |doi=10.1016/j.freeradbiomed.2018.10.450|pmid=30391585 |hdl=10486/688986 |hdl-access=free }}

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.

Immune system is greatly affected by CAFs. CAFs promote the recruitment of monocytes and induce their differentiation into pro-tumorigenic macrophage subset M2. In breast cancer secretion of monocyte chemotactic protein-1, stromal-derived factor 1 and chitinase 3-like 1 is a signal for monocyte migration and differentiation into M2 subset. Similar effect was observed in prostate carcinoma. In pancreatic cancer, other cytokines have central role in monocyte differentiation into M2 subset such as M-CSF1, IL-6 and CCL2. Other cytokines such as IL-8, IL-10, TGF-β also participate. Such M2 macrophages then further activate progression of CAFs.{{cite journal | vauthors = Liu T, Han C, Wang S, Fang P, Ma Z, Xu L, Yin R | title = Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy | journal = Journal of Hematology & Oncology | volume = 12 | issue = 1 | pages = 86 | date = August 2019 | pmid = 31462327 | pmc = 6714445 | doi = 10.1186/s13045-019-0770-1 | doi-access = free }}

CAFs have inhibitory effects on NK cells by releasing prostaglandin E2 (PGE2). In hepatocellular carcinoma besides PGE2, indoleamine 2,3-dioxygenase (IDO) is suppressing NK cells.

In the restriction of anti-tumor immunity are crucial regulatory T cells (Treg; Foxp3+). CAFs stimulate migration, induction and maintenance of Treg cells which depends on the chemokines CCL5 and CXCL12.

Critical for anti-tumor immunity are cytotoxic CD8+ T cells. CAFs decrease their infiltration into tumor by releasing chemokine CXCL12 and cytokines IL-6 and TGF-β. However, for T cell movement restriction in tumors is also responsible hypoxia, which leads to decrease of expression of adhesion molecules on endothelial cells. 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. CAFs in pancreatic cancer upregulate PD-1, CTLA-4 or TIM-3 on both CD4+ and CD8+ T cell surfaces.

Angiogenesis is an essential aspect of tumour development. In order for a tumour to grow and significantly increase in size, it must have a sufficient blood supply. If the tumour is unable to develop the blood supply it requires, cells within the tumour will begin to die and further growth will be halted. Angiogenic factors such as vascular endothelial growth factor (VEGF), stromal cell-derived factor 1 (SDF-1), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are expressed by CAF to encourage the growth of new blood vessels. Some of these factors may also recruit cells that are vital to the angiogenic process, for instance SDF-1 attracts bone-marrow derived endothelial cells.{{cite journal | vauthors = Kalluri R | title = The biology and function of fibroblasts in cancer | journal = Nature Reviews. Cancer | volume = 16 | issue = 9 | pages = 582–598 | date = August 2016 | pmid = 27550820 | doi = 10.1038/nrc.2016.73 | s2cid = 22558534 }}

CAF have been found to promote tumour metastasis in numerous ways. Firstly, they may alter gene expression and have been found to upregulate specific genes involved in pro-tumorigenic pathways including heat shock factor 1 (HSF1). They can also interfere with the function of tumour suppressor genes, such as Tumour protein p53, leading to higher rates of cell proliferation due to the loss of control of the cell cycle. 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. The group of proteins known as the matrix metalloproteinases are key to this process. CAF also direct the movement of neoplastic cells by using the Rho-dependent signaling pathway to create tracks for these cells in the matrix.

In some cases, the characteristics of CAF provide therapeutic resistance. Soluble factor resistance occurs when CAF either directly secrete signals (cytokines or growth factors) or influence the cells around them to give off similar signals, which reduce the efficacy of therapeutic drugs. 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. Another form is cell adhesion- mediated drug resistance. This involves the tight attachment of neoplastic cells to the extracellular matrix or stromal cells. For example, secretion of TGF-beta allows cancerous cells to bind more successfully to the extracellular matrix thus evading the action of some cancer drugs.

Category:Connective tissue cells

Category:Tumor

Category:Tumor markers