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Year : 2019  |  Volume : 15  |  Issue : 3  |  Page : 690-692

Metastasis-associated fibroblasts in oral squamous cell carcinoma: An illusion or a reality

Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India

Date of Web Publication29-May-2019

Correspondence Address:
Dr. Anjali P Ganjre
Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_546_17

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 > Abstract 

Fibroblasts at the pre-metastatic site exhibited characteristic trait for creation of metastatic milieu which aid in the formation of distant metastasis, and are called as metastasis associated fibroblasts (MAFs).Array of studies showed that MAF bears similar attributes as that of carcinoma associated fibroblasts present in primary tumor. MAFs showed expression of specific type of molecules and pathways to form required pre-metastatic microenvironment at the distant site. It will be important to unrevealed characteristics features in OSCC so as to help in implicating the new therapeutic strategies.

Keywords: Fibroblasts, metastasis, oral cancer

How to cite this article:
Ganjre AP. Metastasis-associated fibroblasts in oral squamous cell carcinoma: An illusion or a reality. J Can Res Ther 2019;15:690-2

How to cite this URL:
Ganjre AP. Metastasis-associated fibroblasts in oral squamous cell carcinoma: An illusion or a reality. J Can Res Ther [serial online] 2019 [cited 2021 Dec 4];15:690-2. Available from: https://www.cancerjournal.net/text.asp?2019/15/3/690/237388

 > Introduction Top

Carcinoma-associated fibroblasts (CAFs) are responsible for invasion and metastasis. Origin is thought to be from resident local fibroblasts, bone marrow-derived progenitor cells, and transdifferentiating epithelial/endothelial cells through epigenetic transition. They secrete transforming growth factor (TGF) β, matrix metalloproteinases, and other cytokines which found to be responsible for invasion into the adjacent tissues.[1]

Premetastatic niche is the preliminary requirement for the formation of distant metastasis, created by the cells which reside in the local microenvironment.[2] According to Piaget's theory, soil is formed at the distant site by forming favorable condition.[3] Few studies demonstrated that this favorable condition is formed by the cells which are present within the local distant metastatic stroma.[2],[4]In vitro” study showed that fibroblasts present far away at the metastatic site exhibited characteristic trait for the creation of metastatic milieu and could be called as metastasis-associated fibroblasts (MAFs) instead of CAF.[5],[6],[7],[8],[9],[10],[11] It was demonstrated that smooth muscle actin (SMA)-positive MAFs are the cells which bear the property to prepare and maintain premetastatic niche in the distant organ.[5] They create microenvironment in the premetastatic site which results in the dissemination of primary tumor cells to that particular site. It has been demonstrated in breast cancer that fibroblasts near the premetastatic stroma serve as a niche, supporting the metastatic colonization of disseminated carcinoma cells in distant organs. To date, various studies done in oral squamous cell carcinoma (OSCC) showed that CAFs in primary tumor create invasion and metastasis, but the other side of coin should be taken into consideration, stromal cells at metastatic niche are the one which played a significant role in metastasis formation. Thus, it will be valuable to unreveal the importance of premetastatic niche in correlation with the fibroblasts at metastatic site. It will help in tailoring a new therapeutic regimen in OSCC.

 > Attributes of Metastasis-Associated Fibroblasts Top

Studies showed that MAFs could be the real player for the configuration of the metastasis. MAFs exhibit characteristics feature which accountable for metastasis. Diverse studies have found out that MAFs exist [5],[6],[7],[8],[9] and need to be divulged in OSCC.

Experimental data have found out that MAFs showed different and specific “cell of origin” as compared to the CAFs. Precursor mesenchymal cells from metastatic niche differentiated into MAFs by releasing specific cytokines.[5] It was studied in hepatic metastasis of melanoma that the melanoma cells appear to stimulate and transform hepatic stellate cells to myofibroblast-like phenotype with SMA-positive expression and cytoskeletal changes.[12]

Moreover, MAFs exhibited different kinds of responsiveness to specific cytokines. It was demonstrated in colorectal cancer that MAFs formed from portal fibroblasts, and hepatic stellate cells have responded differently and specifically to cytokines such as platelet-derived growth factor (PDGF) and TGF β. Portal fibroblasts indifferent to PDGF, while they inhibited by TGF β.[6]

In vitro” study demonstrated that fibroblasts from specific metastatic site showed an increase in expression of various gene proteins such as proteins for adhesion molecules, cytokines (PDGFA, fibroblast growth factor, monocyte chemoattractant protein-1 [MCP-1], etc.,) which helps indirectly in tumor cell migration and metastasis.[8] Fibroblasts associated with premetastatic site showed differences in expression of TNF and stromal cell-derived factor 1 (SDF1) expression as compared to primary tumor stroma. It was found that fibroblasts from metastatic site exhibit immune positivity for TNF-α which was responsible for neoangiogenesis, while stromal fibroblasts from primary tumor were negative.[9] In liver cancer, resident fibroblasts from metastatic site secrete higher level of SDF1 as compared to primary tumor of the same without metastasis.[8]

Furthermore, TGF α-treated MAFs showed increased expression of interleukin-6, MCP-1, and intercellular adhesion molecule-1 which were found to be associated with the formation of metastasis. An in vitro study demonstrated that when cancer cells stimulated by “TGF-α treated MAF,” tumor cells show enhanced migration.[9]

 > Characteristics of Premetastatic Niche Associated With Fibroblasts Top

Intense studies on premetastatic niche have found that activated fibroblasts (stromal niche) from the distant metastatic site responsible for the colonization of cancer cells which is created by unique composition of local stromal microenvironment.[4] Fibroblasts from metastatic site found to produced specific proteins which drives metastatic colonization of disseminated breast carcinoma cells.[13]

Premetastatic mesenchymal niche enhances fibronectin expression and an increase in “PDGFR-expressing cells” so as to locate tumor cells at predetermined site, before the arrival of cancer stem cells.[12]

A study done by Wakisaka et al. in OSCC showed that premetastatic lymphovascular niche (sinusoidal hyperplasia) appeared before formation of actual metastasis in the lymph nodes. Various tumor models showed that tumor-derived factors stimulate the bone marrow-derived cells to interact with the premetastatic niche stroma in distant organ/lymph nodes to form lymphovascular niche. These lymphovascular niche facilitates tumor cell transport to the lymph nodes and contributes to the migration, residence, and survival of metastatic cancer cells.[2] In primary tumor, CAFs were found to contribute for lymphangiogenesis and angiogenesis.[14] In the same way, it was found that activated stellate cells at metastatic site initiate the angiogenic switch of nascent mesenchymal cells. Subsequently, results in invasion of endothelial cells at the hypoxic condition lead to dissemination of tumor cells. Moreover, infiltrating tumor cells induce stromal POSTN (periostin) expression [13] and tenascin-C (TN-C) proteins in the secondary target organ to initiate colonization.[15] In lung metastasis, fibroblasts produce POSTN proteins which interact with Wnt ligands to augment the presumed signaling activity from tumor cells which drives metastatic colonization of disseminated breast carcinoma cells at the distant site.[16]

 > Interpretation Top

  1. Premetastatic niche in the form of mesenchymal fibroblasts has a crucial influence on the formation of metastasis at the far site
  2. The effect of various molecular signaling on the MAF at distant metastatic site is important. Furthermore, the amount of expression of these cytokines should be evaluated
  3. It is important to differentiate the existence of MAFs from other cellular component in tumor microenvironment in OSCC. More experimental data are required to signify the role of MAFs in the formation of premetastatic niche.

Array of studies in different cancers showed that MAFs have existed at the metastatic site and are actually the activated fibroblasts responsible for metastasis. The characteristic features govern by MAFs are different than the CAFs in tumor stroma. They secrete crucial molecular proteins associated with the formation and maintenance of metastasis. It is a field of research to find out whether these characteristic MAFs are present in the OSCC or not. Its properties associated with metastasis in OSCC are yet to be explored. Our focus of this paper is to draw attention to the facts about the various characteristics govern by MAFs. It will help in revealing many unresolved queries related to metastasis in OSCC. Moreover, it will aid in improving the prognosis of patients by designing novel-targeted therapy.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Cirri P, Chiarugi P. Cancer associated fibroblasts: The dark side of the coin. Am J Cancer Res 2011;1:482-97.  Back to cited text no. 1
Wakisaka N, Hasegawa Y, Yoshimoto S, Miura K, Shiotani A, Yokoyama J, et al. Primary tumor-secreted lymphangiogenic factors induce pre-metastatic lymphvascular niche formation at sentinel lymph nodes in oral squamous cell carcinoma. PLoS One 2015;10:e0144056.  Back to cited text no. 2
Paget G. Remarks on a case of alternate partial anaesthesia. Br Med J 1889;1:1-3.  Back to cited text no. 3
Mueller L, Goumas FA, Affeldt M, Sandtner S, Gehling UM, Brilloff S, et al. Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am J Pathol 2007;171:1608-18.  Back to cited text no. 4
Matsusue R, Kubo H, Hisamori S, Okoshi K, Takagi H, Hida K, et al. Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis. Ann Surg Oncol 2009;16:2645-53.  Back to cited text no. 5
Asahina K. Hepatic stellate cell progenitor cells. J Gastroenterol Hepatol 2012;27 Suppl 2:80-4.  Back to cited text no. 6
Tommelein J, Verset L, Boterberg T, Demetter P, Bracke M, De Wever O, et al. Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer. Front Oncol 2015;5:63.  Back to cited text no. 7
Nakagawa H, Liyanarachchi S, Davuluri RV, Auer H, Martin EW Jr., DeLa, Chapelle A, et al. Role of cancer associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 2004;23:7366-77.  Back to cited text no. 8
Müller L, Schumacher J, Temel B, Von Seggern L, Tiwari S, Kalthoff H, et al. Increased migration of colorectal cancer cells induced by TNF-alpha-treated stromal fibroblasts from human liver metastases. Cell Commun Signal 2009;7:A102.  Back to cited text no. 9
Yoshitake N, Fukui H, Yamagishi H, Sekikawa A, Fujii S, Tomita S, et al. Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer 2008;98:1682-9.  Back to cited text no. 10
Kwak Y, Lee HE, Kim WH, Kim DW, Kang SB, Lee HS, et al. The clinical implication of cancer-associated microvasculature and fibroblast in advanced colorectal cancer patients with synchronous or metachronous metastases. PLoS One 2014;9:e91811.  Back to cited text no. 11
Wels J, Kaplan RN, Rafii S, Lyden D. Migratory neighbors and distant invaders: Tumor-associated niche cells. Genes Dev 2008;22:559-74.  Back to cited text no. 12
Wang Z, Ouyang G. Periostin: A bridge between cancer stem cells and their metastatic niche. Cell Stem Cell 2012;10:111-2.  Back to cited text no. 13
Li H, Zhang J, Chen SW, Liu LL, Li L, Gao F, et al. Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer. Cell Stem Cell 2012;10:111-2.  Back to cited text no. 14
Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr HA, Delaloye JF, et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 2011;481:85-9.  Back to cited text no. 15
Togo S, Polanska UM, Horimoto Y, Orimo A. Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers (Basel) 2013;5:149-69.  Back to cited text no. 16

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