Elsevier

The Breast

Volume 24, Issue 5, October 2015, Pages 532-538
The Breast

Viewpoints and debate
Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy

https://doi.org/10.1016/j.breast.2015.06.009Get rights and content

Abstract

In recent years, mass spectrometry-based proteomics has undergone significant development steps which may be divided into an exploratory phase, a consolidation phase and an application phase. We are in a stage now where we are able to apply mass spectrometric technologies to answer complex and clinically relevant questions. This is demonstrated here with respect to a current hot topic, namely the consideration of the cancer-supporting microenvironment as a target of new and more efficient anti-cancer therapy. Actually, the relevance of micro environmental stromal cells to tumor initiation and promotion has been clearly recognized. However, the individual kind and degree of stroma-derived tumor promotion can so far hardly be determined in patients, and hardly any therapeutic option exists to dismantle the cancer cells of the stroma-derived support. Quite remarkably, the response of stromal cells to standard chemotherapeutics is also rather unknown. In this Perspective, experimental strategies how to address such issues are outlined in detail. Different cell systems are presented as powerful models which allow identifying relevant marker molecules. Targeted proteomics is presented as method of choice for both, drug screening in vitro as well as monitoring drug responses in patients. By this means, a way of classifying different functional tumor promoting mechanisms, evaluating how current treatment strategies may affect cancer-associated fibroblasts, identifying effective drugs targeting these cancer-associated cells and, may be most importantly, demonstrating how combined therapeutic strategies may improve the efficiency of anti-cancer treatments are indicated.

Section snippets

Background and motivation

Breast cancer is the most common type of cancer in women, with incidence rates still on the rise [1]. Since recently, the cancer-associated stroma has gained an increasing importance for many aspects of carcinogenesis, including cancer development and growth, as well as establishment of drug resistance [2], [3]. Cancer-associated fibroblasts (CAFs) seem to be especially critical for many aspects of carcinogenesis [4]. Treatment of these cells may therefore represent a new option for anti-cancer

The research hypothesis

A rather simple hypothesis is the fundament of this Perspective (Fig. 1A). The classical therapeutic strategy rather targets cancer cells only. Indeed, in most cases the first-line chemotherapy is very successful in massively reducing the bulk of cancer mass. However, if the stromal microenvironment has adopted a tumor-promoting phenotype, the re-establishment of tumor growth from few cancer cells evading first-line chemotherapy is highly probable. It is actually the relapse of the disease what

Research strategies

When basic research results should be translated into applications, several important hierarchical evaluation steps need to be considered (Fig. 1B). First of all, the pathophysiological mechanism which shall be corrected needs to be largely understood. If this is accomplished, suitable model systems representing these mechanisms need to be established. A critical question refers to the relevance of such model systems: are the processes investigated with cell models actually really close to

Significance

Basic research has clearly identified a determining role of the tumor-associated stroma in disease progression. This Perspective outlines feasible experimental strategies to determine whether and how targeting the tumor-associated stroma may contribute to an improved anti-cancer therapy. The gap between basic research and clinical applications may thus be bridged by the application of latest and technically mature proteome analysis methods.

Conflict of interest statement

The authors declare no competing financial interests.

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