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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 17  |  Issue : 1  |  Page : 170-174

Cancer-associated fibroblasts and FAP-Alpha: Its applications in odontogenic tissues


1 Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. Patil University, School of Dentistry, Nerul, Navi Mumbai, Maharashtra, India
2 Department of Oral and Maxillofacial Pathology and Microbiology, Dr. D. Y. Patil University School of Dentistry, Navi Mumbai, Maharashtra, India

Date of Submission18-Dec-2021
Date of Decision03-Mar-2022
Date of Acceptance08-Mar-2022
Date of Web Publication25-Jul-2022

Correspondence Address:
Dr. Sandhya Tamgadge
Department of Oral and Maxillofacial Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Sector 7, Nerul, Navi Mumbai - 400 706, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdmimsu.jdmimsu_467_21

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  Abstract 


Cancer has always been a mystery for researchers, health-care providers and even patients. The entire journey of a cell from physiological to pathological form has been incompletely explored. Everyday new research articles have been updated on various platforms where researchers have been making an attempt to find out the various causes of carcinogenesis. Cancer-associated fibroblasts and its one of the prime proteins FAP (FIBROBLAST ACTIVATION PROTEIN ALPHA) alpha found in the normal-appearing tumor microenvironments have been investigated by many researchers and showed a positive correlation with advanced tumor grade. It has been found highly expressive in oral squamous cell carcinoma. Odontogenic lesions too are highly destructive and show recurrence. There is a need to evaluate FAP-alpha expression in these lesions too.

Keywords: Cancer-associated fibroblasts, cysts, FAP-alpha, odontogenic tissues, tumor microenvironment


How to cite this article:
Tamgadge S, Pereira T. Cancer-associated fibroblasts and FAP-Alpha: Its applications in odontogenic tissues. J Datta Meghe Inst Med Sci Univ 2022;17:170-4

How to cite this URL:
Tamgadge S, Pereira T. Cancer-associated fibroblasts and FAP-Alpha: Its applications in odontogenic tissues. J Datta Meghe Inst Med Sci Univ [serial online] 2022 [cited 2022 Aug 18];17:170-4. Available from: http://www.journaldmims.com/text.asp?2022/17/1/170/352245




  Introduction Top


Epithelial cancer research was earlier primarily focused only on various components of neoplastic epithelial cells. Despite marked development in cancer therapies during recent decades, the prognosis for advanced cancer remains poor. Therefore, current studies have suggested that normal-appearing “tumor microenvironment (TME) too plays a vital role in the progression of tumors.”[1]

The conventional tumor cell-centric view of cancer can only explain part of cancer progression, and thus, a thorough understanding of the TME is crucial. Among cells within the TME, cancer-associated fibroblasts (CAFs) are attracting attention as a target for cancer therapy.[2]

TME which immediately surrounds the tumor certainly decides whether cancer will win or lose the battle. It comprises all the tissue components similar to the healing phase in wounds but the fibroblasts in it are activated and promote the neoplastic process.[3]

Precancerous and cancer lesions of epithelial origin of orofacial lesions are mostly caused by harmful agents such as tobacco, betel nut, etc., which act on surface mucosa. Surface hyperkeratosis is the body's protective mechanism against the harmful effect of tobacco.[4]

These agents cause cellular alterations in the form of epithelial dysplasia. Such dysplastic features should start from surface mucosa because carcinogens attack primarily surface mucosa during its consumption. Surprisingly, it starts from the basal layer and progresses upward toward the surface. Therefore, we can say that these harmful chemicals act predominantly through systemic or internal routes. Thus, the TME has an important role to play in carcinogenesis for epithelial malignancies.[5]

Fibroblasts are the prominent nonspecialized cells of the stroma. They exist in physiological (first) and activated (second) form both.[2],[3]

In physiological (first), they acquire transient activity during periods of tissue remodeling and repair. These activated fibroblasts will then either undergo apoptosis or revert back to a dormant state, if not, pathological (second) forms such as tissue fibrosis and chronic inflammation can arise. This chronic tissue repair response leads to progression to cancer. Activated fibroblasts that surround tumors are termed CAFs and they, along with other elements of the TME, can indulge in reciprocal dialogues with the neoplastic epithelial cells to maximize tumor fitness.[3]

The only difference between the two tissues is that normal tissue fibroblasts in healing wounds are hijacked by CAFs in the neoplastic tissue. Therefore, such tumors are considered “wounds that do not heal.”[6]

The role of TME is confirmed by several studies demonstrating the association between gene expression patterns of microenvironmental cell types and prognosis in patients with breast, lung, and colorectal cancer. CAFs are among the most abundant cell types within a range of different tumor types, and the accumulating evidence points to a fundamental role for CAFs in influencing the malignant phenotype.[7]

Conversely, it is also reported that CAFs can be reprogrammed. Phenotype indicating that the transition is reversible. CAF phenotypes are considered to be a cellular state of the fibroblast, not a fixed cell type.[7],[8]


  Definition of Cancer-Associated Fibroblasts Top


CAFs are defined as spindle-shaped cells, which are negative for epithelial, endothelial, and leukocyte markers derived from cancer tissue.[9]

They are located within or in proximity to the tumor mass. They protect cancer cells from host immune attacks. Vimentin is considered to be a marker for quiescent CAFs, There are many biomarkers secreted by CAF such as:[8],[9]

  1. Neutral biomarkers with dual functions-α-smooth muscle actin (α-SMA), S100A4
  2. Accomplices: Protumorigenesis biomarkers


    • FAP
    • Platelet-derived growth factor receptor α/β (PDGFRα/β)
    • PDPN
    • CD70
    • Vimentin
    • GPR77
    • CD10
    • CD74


  3. Defenders: Tumor-suppressive biomarkers


  • CD146
  • CAV1
  • Saa3


It has been reported that normal fibroblasts can acquire a CAF phenotype.[7]


  Potential Cellular Sources Of Cancer-Associated Fibroblasts Top


Several cell types may transit to the tumor or differentiate in situ and become CAFs around tumor cells.[10]

CAFs may have diverse origins, including (a) tissue-resident fibroblasts, (b) cellstrans-differentiated from other cell types such as endothelial cells, epithelial cells, vascular smooth muscle cells, pericytes, adipocytes,[10],[11],[12] and their progenitors, (c) cancer cells trans-differentiated to mesenchymal cells through EMT, and (d) bone marrow (BM)-derived precursors and BM mesenchymal stem cells.[11]

CAFs were originally presumed to represent a homogeneous population uniformly driving tumorigenesis. However, in sophisticated in vitro and in vivo experiments, and, more recently, it is now widely appreciated that CAFs form a group of highly heterogeneous cells with no single overarching marker.[2]

Classification

Classification of CAFs has been tried by various researchers to develop novel CAF-targeted therapies.[8]


  Birth of Cancer-Associated Fibroblasts Top


As suggested by Colleen Fordyce et al. p53/activin A/cyclooxygenase-2 (COX-2)-dependent DNA damage pathway emerge in epithelial cells that elicits protumorigenic effects in neighboring fibroblasts through paracrine stimulation via activin A.

Activation of fibroblasts by activin A triggers a spectrum of COX-2-driven protumorigenic phenotypes, including ECM remodeling, angiogenesis, immune influx, macrophage switch, cell proliferation, DNA damage, and acquisition of a hypoxic/glycolytic microenvironment.

Dysregulated signaling pathways include upregulation of transforming growth factor-beta, bone morphogenic protein, Wnt, Sonic hedgehog, PDGF, C-X-C motif ligand 12 (CXCL12)/CXCR4, and integrin-mediated signaling.

CAF-specific protein expression levels change upon acquisition of the CAF phenotype. Changes in protein expression include upregulation of α-SMA, fibroblast-activating protein (FAP), fibroblast-specific protein-1, PDGF receptor a (PDGFRa), PDGFRb, Forkhead box F1 (FOXF1), SPARC, Podoplanin (PDPN), and, more recently, collagen 11-α1 (COL11A1) and microfibrillar-associated protein 5 and down-regulation of CD36,[5]

Cancer-associated fibroblast clinical trial activity

In some cases, new strategies are being developed to target fibroblasts specifically (for example, fibroblast activation protein (FAP) ligands coupled to cytotoxic drugs.[1]

Thus, there is an urgent need for the development of new and effective cancer therapies fuelled by conceptually transformative basic science. The surrounding TME coevolves during the malignant progression into an activated state through paracrine, juxtacrine, and autocrine communications.[10]

Out of which highly researched markers are alpha-SMA which has contractile ability and produces extracellular matrix compounds and second is FAP-alpha which plays a major role in ECM remodeling.[8]

The cross-talk between tumor cells and (CAFs, alternatively termed activated fibroblasts) is crucial in regulating the drug resistance, tumorigenesis, neoplastic progression, angiogenesis, invasion, and metastasis of a tumor.[11]

Alpha a-SMA and FAP-alpha have been comparatively researched more in various tumors.

FAP

It was first described in 1986 by Rettig et al. found at the invasive front of tumor, healing wounds, chronic inflammation, and fibrotic conditions.[12]

Synonyms for FAP gene

  1. Fibroblast activation protein alpha
  2. Seprase
  3. 170 KDa melanoma membrane-bound gelatinase
  4. Gelatine degradation protease FAP
  5. Integral membrane serine protease
  6. Postproline cleaving enzyme
  7. Surface Expressed Protease
  8. Prolyl endopeptidase FAP
  9. Dipeptidyl peptidase FAP
  10. FAPalpha
  11. DPPIV
  12. SIMP
  13. FAPA
  14. FAP[1],[3],[14]


Structure of the FAP-α protein

FAP molecule consists of 6 amino acid cytoplasmic tail, a single 20 amino acid transmembrane domain, and a 734 amino acid extracellular domain. FAP exists as a dimer both on the cell surface and blood in human plasma. Little is known about the exact origin of circulating FAPa. FAP-a is located on chromosome 2q23 and is a potential therapeutic target in cancer.[11],[12],[13],[14],[15],[16]

The embryonic origin of most fibroblasts is mesoderm[3] with a smaller subset of fibroblasts also derived from the neural crest, which is part of the ectoderm.[8],[11],[17]

FAP-alpha activity-FAP Dual-enzyme activity:[15],[17]

  1. Dipeptidyl peptidase – the activity of FAP allows it to cleave two amino acids off the N-terminus of a protein. This cleavage occurs after a proline (Pro) residue
  2. Endopeptidase activity of FAP enables cleavage that is more than two amino acids from the N-terminus of a protein. Cleavage is restricted to the post-Pro bond after glycine-Pro (Gly-Pro)


Above two activities helps the neoplastic cell to invade and metastasize.

FAP-alpha research in oral tissues:

  1. Normal tissues


  2. Periodontal ligament exhibited strong expression of genes FAP related to collagen synthesis. FAP-alpha expression has been studied in the dental pulp tissue and stem cells using FAPa + staining in the plasma membrane. Immunocytochemistry staining of FAPa in cultured dental papilla stem cells showed localization in the plasma membrane or limited to the pseudopodia.[18],[19]

  3. FAP-alpha expressions in various tumors


Research on FAP-alpha in oral lesions has been sparse. In oral squamous cell carcinoma (OSCC), high FAP expression was reported to associate with higher tumor stage, lymph node metastasis, and reduced overall survival. Interestingly, another study in OESCC found that low FAP levels in plasma.[20],[21],[22]


  Target Therapy Top


1) CAFs are increasingly viewed as a target that could be manipulated for therapeutic benefit in patients with cancer In some cases, new strategies are being developed to target fibroblasts specifically (for example, fibroblast activation protein (FAP) ligands coupled to cytotoxic drugs.

Current status Phase I and Phase II trials f. 182), under way.[23]

2) Research on FAP vaccines in mouse models.(DNA vaccine directed against FAP).

FAP vaccines cell-mediated killing of the target cells in mouseCT26 colon carcinoma and D2F2 breast carcinoma models dendritic cell vaccines have been utilized to elicit effective immune responses that would eliminate FAP-positive cells.[17],[21]

An orally administered DNA vaccine (S. typhimurium transformed with a vector encoding mouse FAP) decreased tumor growth.[17],[21]

FAP alpha and odontogenic lesions

Odontogenesis is a process which involves highly synchronized epithelial–mesenchymal interactions for tooth development within the jaw. The tissue of origin for the odontogenesis is nothing but the overlying the oral mucosa of the fetal jaw. This overlying mucosa covering edentulous fetal jaw proliferates and enters the jaw in such a way that at future teeth positions, it forms localized knobs which are called as tooth buds.[24]

Thus, oral mucosa and odontogenesis are strongly connected. Various epithelial malignancies including oral squamous cell carcinoma have been studied including using FAP-alpha. Therefore, odontogenic cysts and tumors both benign and malignant forms behave aggressively and recur.[25] Hence, they should also be evaluated for FAP-alpha to explore more biomolecules in the tissue microenvironment because of the following reasons:

  • Molecular etiopathogenesis is still not completely understood
  • Though benign but behaves aggressively
  • Recurrence is frequent
  • There are tremendous epithelial–mesenchymal interaction right from tooth germ stage to cystic and neoplastic transformation
  • Immature stroma (tooth germ stage) is replaced by mature stroma during cystic and neoplastic transformation
  • Therefore, stromal fibroblasts should be evaluated to find out FAP-alpha expression which has not been done yet
  • Ameloblasts-associated fibroblasts (AAFs) by Chantravekin et al have been studied in cell culture. This study supports the proliferation of the tumor cells and has a tendency to stimulate the proliferation and induce the invasion. Increased levels in the CAF condition media were also detected suggesting the possible role of this growth factor in ameloblastoma biology[26]


This marker has also been researched as radiotracer. A single radiotracer can identify nearly 30 types of cancer, allowing for new applications in noninvasive diagnosis, staging, and treatment, according to research presented at the 2019 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI).[1]

The results of the study demonstrate that positron emission tomography/computed tomography (PET/CT) with a fibroblast-activation protein inhibitor (FAPI) – which targets the overexpressed proteins present in cancer – resulted in images with exceptionally clear tumor delineation and high image contrast, as demonstrated in the 68Ga-FAPI-PET/CT image that has been selected as the 2019 SNMMI Image of the year.[1]

Key recommendations for CAF research:

  1. recording of CAF numbers in clinical studies and trials, starting with reporting of α- smooth muscle actin (αSMa) and fibroblast activation protein (FaP) staining
  2. Recording of CAF numbers in clinical studies and trials[23]



  Conclusion Top


Most of the odontogenic tumors and cysts behave aggressively, recur and cause much destruction. There has been a lot of research on various aspects of biomolecules and genetic constituents present within an epithelial component of odontogenic lesions. Stromal component has also been an area of research for many researchers. However, evaluation of FAP-alpha has not been done for this group of lesions. There is a need to evaluate this association.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Definition of Ca...
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Birth of Cancer-...
Target Therapy
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