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 Table of Contents  
Year : 2018  |  Volume : 13  |  Issue : 2  |  Page : 116-117

Role of carcinoma-associated fibroblasts in “anoikis resistance” for oral squamous cell carcinoma: Need of the hour

Department of Oral Pathology & Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India

Date of Web Publication23-Nov-2018

Correspondence Address:
Dr. Anjali P Ganjre
Dr. D. Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Sant Tukaram Nagar, Pimpri, Pune - 411 018, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdmimsu.jdmimsu_6_16

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How to cite this article:
Ganjre AP. Role of carcinoma-associated fibroblasts in “anoikis resistance” for oral squamous cell carcinoma: Need of the hour. J Datta Meghe Inst Med Sci Univ 2018;13:116-7

How to cite this URL:
Ganjre AP. Role of carcinoma-associated fibroblasts in “anoikis resistance” for oral squamous cell carcinoma: Need of the hour. J Datta Meghe Inst Med Sci Univ [serial online] 2018 [cited 2019 Apr 20];13:116-7. Available from: http://www.journaldmims.com/text.asp?2018/13/2/116/246013


Anoikis is a protective mechanism against invasion and metastasis.[1] Anoikis resistance (AR) is a major beneficial quality governs by cancer cells as it bears intrinsic characteristics for metastasis.

Tumor microenvironment plays a crucial role in tumor progression, invasion, and metastasis. Array of research found out that carcinoma-associated fibroblasts (CAFs), which showed myofibroblast (MF)-like features, are responsible for cancer invasion and metastasis.[2],[3] CAFs help cancer cells to travel to distant site through metastasis by inhibiting anoikis of tumor cells.[4]

AR occurs in oral squamous cell carcinoma (OSCC) through array of mediators.[5] It has been proved that CAFs cause AR in breast cancer. CAFs help cancer cells to evade anoikis. However, effect of CAFs on cancer cells for anoikis in OSCC is a field of research as anoikis-resistant OSCC cell lines display a unique karyotypic and genotypic fingerprint that differs from anoikis-sensitive OSCC cells.[5] Hence, for the first time, we would like to focus the light on interrelationship of CAFs and molecular pathway in AR phenomenon responsible for metastasis. Many a time, CAFs showed chemoresistant property for OSCC patients. Hence, revealing the role of CAFs in anoikis phenomenon will help in providing a new roadway for therapeutic purpose.

  Different Molecular Pathways For Anoikis Resistance via Carcinoma-Associated Fibroblasts Top

Epithelial–mesenchymal transition (EMT) is a key process for metastasis and exhibits an essential characteristic for AR. It is associated with increase in expression of proteins such as N-cadherins and smooth muscle actin.[6] It was found that N-cadherins were able to induced AR in tumor cells.[7]

CAFs play the role in AR through various mechanisms for cancer cells.

CAFs facilitate invasion via EMT. Expression of transforming growth factor (TGF)-β via CAFs induces EMT which results in downregulation of E-cadherins and upregulation of N-cadherins, which leads to AR.[1],[8],[9] Furthermore, it was found that TGF-β expressed via CAFs is responsible for loss of E-cadherin which results in the prevention of anoikis as E-cadherin-interacting protein, ankyrin-G, arbitrates anoikis regulatory signals.[10]

CAFs govern two vital processes for EMT which helps in overcoming anoikis. First, they secrete matrix metalloproteinase 2 and 9 which were found to cleave the E-cadherins. Second, CAFs aid in release of reactive oxygen species via Rac1b/cyclooxygenase-2 pathways which helps the cancer cells to overcome anoikis for EMT.[11]

TGF-β and fibroblast growth factor-2 (FGF-2) assist with each other and regulate EMT during cancer progression. During EMT, TGF-β induces isoform switching of FGF receptors, causing the cells to become sensitive to FGF-2 and forme “activated fibroblast” by promoting the formation of complexes between Zeb1 and with CtBP1 phosphorylated through the FGF-2-activated MEK-ERK pathway. Activated ERK pathway triggers factor Zeb via upregulation of Fra1 which is responsible for EMT by inhibiting anoikis of malignant cells. Concurrently, cancer cells invade and metastasize at distant site in cooperation with activated fibroblasts.[10]

Research has proved that “anoikis-resistant CAFs” inhibit anoikis of cancer cells by paracrine signaling and carry them to distant site for metastasis.[12],[13]

A study done by Horowitz et al. proved that TGF-β prevents anoikis of MFs. TGF-β1 induces rapid activation of P13/Akt pathway. Activation of P13/Akt pathway is mediated by p38 mitogen-activated protein kinase (MAPK)-dependent production of growth factors which acts in an autocrine/paracrine mechanism. Thus, initiation of P13/Akt pathway results in induction of “anoikis-resistant phenotype” to MF at the time of EMT.[12]

A detailed study on anoikis and MF proved that TGF-β regulates SMAD-mediated N-cadherin expression for EMT. TGF-β has a coordinated and independent role in the activation of focal adhesion kinase and Akt kinase pathways through the stimulation of SMAD3 and p38 MAPK factors for endowing “anoikis-resistant phenotype” to MF.[13]

Researchers found out that CAFs have stabilizing effect on antiapoptotic proteins which are responsible for anoikis. A study done on breast cancer cells revealed critical role of CAFs in blocking anoikis through insulin-like growth factor receptor (IGFR). CAFs stabilize Mcl-1 antiapoptotic protein via IGFR and inhibit anoikis of cancer cells through paracrine manner.[4]

Kim et al. revealed that invasive breast cancer cells granted an anoikis-resistant phenotype on MF during tissue remodeling by activating laminin-332 upregulation and neoexpressing integrin-β4. Two mechanisms were put forward; indirect interaction and direct interaction. In indirect interaction, factors released from cancer cells increase the expression of laminin-332 by MF. Laminin-332 binds to integrin α3 β1 present on MF and “switch on” the autocrine cell survival signal through Akt pathway. Direct interaction involved the direct contact between invasive breast cancer cells and MF results in induction of neoexpression of integrin-β4. MF cell survival signals were mediated by Rac1 activation and Akt phosphorylation.[14]

  Interpretation Top

  1. In epithelial cancer, AR is essential to set free from epithelium
  2. In OSCC, lymph node metastasis is because of mobility of cancer cells by modulating actin cytoskeleton and forming invadopodia
  3. From various studies, it is evident that CAFs controls the motility of cancer cells by regulating pathways such as Akt, SMAD, and MAPK involved in AR
  4. CAFs indirectly and directly control the expression of array of molecules for AR.

Interrelationship between CAFs and AR has a definitive role in metastasis. Till now, CAFs have been explored in OSCC in array of roles; however, its role for AR has still to be explored and conceptualized. AR has a major impact on prognosis of the patient as it is a prerequisite for metastasis. A direct role of CAFs on anoikis is yet to unravel in OSCC which bears a distinct effect on cancer cell survival during invasion. A better understanding of molecular mechanism involved in AR via CAFs to overcome metastasis would help in the formation of novel anticancer approach to attained better prognosis.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Kim YN, Koo KH, Sung JY, Yun UJ, Kim H. Anoikis resistance: An essential prerequisite for tumor metastasis. Int J Cell Biol 2012;2012:306879.  Back to cited text no. 1
Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 2010;9:3256-76.  Back to cited text no. 2
Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, et al. Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo. PLoS One 2014;9:e89605.  Back to cited text no. 3
Weigel KJ, Jakimenko A, Conti BA, Chapman SE, Kaliney WJ, Leevy WM, et al. CAF-secreted IGFBPs regulate breast cancer cell anoikis. Mol Cancer Res 2014;12:855-66.  Back to cited text no. 4
Bunek J, Kamarajan P, Kapila YL. Anoikis mediators in oral squamous cell carcinoma. Oral Dis 2011;17:355-61.  Back to cited text no. 5
Nagafuchi A, Shirayoshi Y, Okazaki K, Yasuda K, Takeichi M. Transformation of cell adhesion properties by exogenously introduced E-cadherin cDNA. Nature 1987;329:341-3.  Back to cited text no. 6
Li G, Satyamoorthy K, Herlyn M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 2001;61:3819-25.  Back to cited text no. 7
Pavlides S, Vera I, Gandara R, Sneddon S, Pestell RG, Mercier I, et al. Warburg meets autophagy: Cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid Redox Signal 2012;16:1264-84.  Back to cited text no. 8
Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ, Feng YM, et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br J Cancer 2014;110:724-32.  Back to cited text no. 9
Shirakihara T, Horiguchi K, Miyazawa K, Ehata S, Shibata T, Morita I, et al. TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J 2011;30:783-95.  Back to cited text no. 10
Giannoni E, Bianchini F, Calorini L, Chiarugi P. Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal 2011;14:2361-71.  Back to cited text no. 11
Horowitz JC, Lee DY, Waghray M, Keshamouni VG, Thomas PE, Zhang H, et al. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem 2004;279:1359-67.  Back to cited text no. 12
Diamond ME, Sun L, Ottaviano AJ, Joseph MJ, Munshi HG. Differential growth factor regulation of N-cadherin expression and motility in normal and malignant oral epithelium. J Cell Sci 2008;121:2197-207.  Back to cited text no. 13
Kim BG, Gao MQ, Choi YP, Kang S, Park HR, Kang KS, et al. Invasive breast cancer induces laminin-332 upregulation and integrin β4 neoexpression in myofibroblasts to confer an anoikis-resistant phenotype during tissue remodeling. Breast Cancer Res 2012;14:R88.  Back to cited text no. 14


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