Markers of breast cancer stromal fibroblasts in the primary tumour site associated with lymph node metastasis: a systematic review including our case series.
CAFs (cancer-associated fibroblasts), the most abundant cell type in breast cancer stroma, produce a plethora of chemokines, growth factors and ECM (extracellular matrix) proteins, that may contribute to dissemination and metastasis. Axillary nodes are the first metastatic site in breast cancer; however, to the present date, there is no consensus of which specific proteins, synthesized by CAFs, might be related with lymph node involvement. The purpose of this study was to perform a systematic review of CAF biomarkers associated with the presence of regional metastasis. PubMed was searched using the words: 'breast cancer' and 'lymph node' and fibroblast or stroma or microenvironment. After exclusions, eight studies evaluating biomarkers immunoexpression in CAFs and lymph node status were selected. Biomarkers evaluated in these studies may be divided in two groups, according to their ontology: extracellular matrix components [MMP13 (matrix metalloproteinase 13), TIMP2 (tissue inhibitor of metalloproteinases-2), THBS1 (thrombospondin 1), LGALS1 (lectin, galactoside-binding, soluble, 1)] and response to wounding [PDPN (podoplanin), PLAU (plasminogen activator, urokinase), PLAUR (plasminogen activator, urokinase receptor), CAV1 (caveolin 1), THBS1, LGALS1]. A positive expression of MMP13 and LGALS1 in CAFs was associated with enhanced OR (odds ratio) for regional metastasis. Contrariwise, CAV1 positive staining of fibroblasts was associated with decreased OR for nodal involvement. Expression of MMP13, PDPN and CAV1 was further tested in a new series of 65 samples of invasive ductal breast carcinomas by immunohistochemistry and no association between biomarkers expression in CAFs and nodal status was found. It was suggested that breast cancer subtypes may differentially affect CAFs behaviour. It would be interesting to evaluate the prognostic significance of these biomarkers in CAFs from different tumour types.
*Departamento de Radiologia e Oncologia, Disciplina de Oncologia, Faculdade de Medicina da Universidade de São Paulo (LIM-24), São Paulo, Brasil.
Maria Aparecida Azevedo Koike
MA
Folgueira
*Departamento de Radiologia e Oncologia, Disciplina de Oncologia, Faculdade de Medicina da Universidade de São Paulo (LIM-24), São Paulo, Brasil.
Simone
S
Maistro
*Departamento de Radiologia e Oncologia, Disciplina de Oncologia, Faculdade de Medicina da Universidade de São Paulo (LIM-24), São Paulo, Brasil.
Maria Lucia Hirata
ML
Katayama
*Departamento de Radiologia e Oncologia, Disciplina de Oncologia, Faculdade de Medicina da Universidade de São Paulo (LIM-24), São Paulo, Brasil.
Rosimeire Aparecida
RA
Roela
§Departamento de Patologia, Universidade do Vale do Sapucaí, Pouso Alegre, MG, Brasil.
Fiorita Gonzales Lopes
FG
Mundim
‡Departamento de Anatomia Patológica, Hospital A.C. Camargo, São Paulo, Brasil.
Suely
S
Nanogaki
†Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Geertruida H
GH
de Bock
*Departamento de Radiologia e Oncologia, Disciplina de Oncologia, Faculdade de Medicina da Universidade de São Paulo (LIM-24), São Paulo, Brasil.
M Mitzi
MM
Brentani
D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000556:secondary*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D037483:Galectin 1; D006801:Humans; D008207:Lymphatic Metastasis; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016017:Odds Ratio; D017154:Stromal Cells / Q000378:metabolism
D014408:Biomarkers, Tumor; D037483:Galectin 1; C445499:LGALS1 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13