Viewpoints and debateTargeting breast cancer-associated fibroblasts to improve anti-cancer therapy
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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2024, Biochemical PharmacologyCancer associated fibroblast mediated chemoresistance: A paradigm shift in understanding the mechanism of tumor progression
2020, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Studies on the role of CAFs report that targeting only cancer cells for therapeutic success is insufficient without their microenvironment [14]. CAFs, which have a major role in promoting chemotherapeutic resistance, should be targeted along with the cancer cells in combinatorial treatment [15]. Therefore, in the present scenario, many studies have focused on the role of CAFs in oncogenic advancement.
Curcumin exerts its antitumor effects in a context dependent fashion
2018, Journal of ProteomicsCitation Excerpt :These cells are rather predominant in the tumor microenvironment and, in case of breast cancer, typically display a wound healing signature [17]. Based on the interplay between tumor cells and CAFs in vivo, co-culture models of cancer and stromal cells may hold great potentials to investigate drugs potentially affecting both normal and tumor cells [18]. As demonstrated recently by us, proteome profiling represents a qualified approach to investigate tumor-CAFs interactions, despite the complexity and challenging interpretation of the resulting data [19–22].
Metabolic exchanges within tumor microenvironment
2016, Cancer LettersCitation Excerpt :In keeping with these observations clear bidirectional interplay between CAFs and cancer associated macrophages has been also reported [23]. Beside inflammation and hypoxia, stress-delivered catecholamine stimulation has also been indicated as responsible for stromal reactivity and cancer progression, although the metabolic implications have not been investigated [60,61]. Moreover, tunneling mitochondria deserves a mention in this section.
Contribution of human fibroblasts and endothelial cells to the hallmarks of inflammation as determined by proteome profiling
2016, Molecular and Cellular ProteomicsCitation Excerpt :In addition, different categories of markers were defined here that can be used for different applications (Table II): (1) blood-borne markers, i.e. proteins that are secreted by cells in the extracellular space but which do not bind to the extracellular matrix; those may be indicative for a specific inflammatory activated cell type in blood samples, using for example ELISA; (2) membrane-bound proteins from the cell surface, which can be used for FACS analyses; (3) intracellular proteins that canbe used for immunohistochemistry or immunofluorescence. Quantitative monitoring of such markers in clinical samples or appropriate model systems (46) may also help to reveal changes in the functional state of cells in response to specific treatment and, consequently, support the evaluation of specific drug effects. Another important aim was to determine functionalities related to inflammation, which may be specific for stromal cells.