Markers of breast cancer stromal fibroblasts in the primary tumour site associated with lymph node metastasis: a systematic review including our case series

Maria Aparecida Azevedo Koike Folgueira,Maria Lucia Hirata Katayama,M Mitzi Brentani,Suely Nanogaki,Simone Maistro,Fiorita Gonzales Lopes Mundim,Geertruida H De Bock,Rosimeire Aparecida Roela

doi:10.1042/bsr20130060

Abstract

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.

Highlights

There is increasing evidence that breast cancer behaviour reflects an interconnection between the malignant epithelial compartment and the surrounding microenvironment.In contrast with normal physiological stroma, which maintains epithelial cell polarity and inhibits epithelial cell growth and transformation, tumour stroma may stimulate the whole tumour development process [1]
A recent study classifying tumour stroma found that collagen and fibroblast dominant groups were associated with poor outcome [4]
The aim of this study was to address the following question: Does the expression of stromal cell biomarkers increase the risk of presenting lymph node metastasis in breast cancer?

Summary

Introduction

There is increasing evidence that breast cancer behaviour reflects an interconnection between the malignant epithelial compartment and the surrounding microenvironment. In contrast with normal physiological stroma, which maintains epithelial cell polarity and inhibits epithelial cell growth and transformation, tumour stroma may stimulate the whole tumour development process [1]. Folgueira and others associated with worse prognosis in breast cancer [2, 3]. A recent study classifying tumour stroma found that collagen and fibroblast dominant groups were associated with poor outcome [4]

Objectives

Methods

Results

Conclusion