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Prospective dual role of mesenchymal stem cells in breast tumor microenvironment

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Abstract

Breast cancer tissue is a heterogeneous cellular milieu comprising cancer and host cells. The interaction between breast malignant and non-malignant cells takes place in breast tumor microenvironment (TM), and has a crucial role in breast cancer progression. In addition to cellular component of TM, it mainly consists of cytokines released by tumor cells. The tumor-tropic capacity of mesenchymal stem cells (MSCs) and their interaction with breast TM is an active area of investigation. In the present communication, the interplay between the breast resident adipose tissue-derived MSCs (B-ASCs) and breast TM was studied. It was found that a distinct subset of B-ASCs display a strong affinity for conditioned media (CM) from two breast cancer cell lines, MDA-MB 231 (MDA-CM) and MCF-7 (MCF-CM). The expressions of several cytokines including angiogenin, GM-CSF, IL-6, GRO-α and IL-8 in MDA-CM and MCF-CM have been identified. Upon functional analysis a crucial role for GRO-α and IL-8 in B-ASCs migration was detected. The B-ASC migration was found to be via negative regulation of RECK and enhanced expression of MMPs. Furthermore, transcriptome analysis showed that migratory subpopulation express both pro- and anti-tumorigenic genes and microRNAs (miRNA). Importantly, we observed that the migratory cells exhibit similar gene and miRNA attributes as those seen in B-ASCs of breast cancer patients. These findings are novel and suggest that in breast cancer, B-ASCs migrate to the proximity of tumor foci. Characterization of the molecular mechanisms involved in the interplay between B-ASCs and breast TM will help in understanding the probable role of B-ASCs in breast cancer development, and could pave way for anticancer therapies.

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Acknowledgments

We would also like to give special thanks and express our gratitude to Drs. Edward Newsome, Douglas Slakey, and Subramanyam Murthy for their valuable contributions to this study. In addition, we would also like to acknowledge Tulane’s Cancer Center for providing us with the flow cytometry facilities. This work was supported by funds from the Alliance of Cardiovascular Researchers (Grant: M1-545856A1).

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Authors and Affiliations

  1. Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA

    Christiane Senst, Timo Nazari-Shafti, Stefan Kruger, Philipp M. Wörner, Eckhard U. Alt & Reza Izadpanah

  2. Department of Microbiology and Immunology, Tulane University Health Sciences Center, New Orleans, LA, USA

    Kirstin Höner Zu Bentrup

  3. Department of Surgery, Tulane University Health Sciences Center, New Orleans, LA, USA

    Abigail E. Chaffin & Reza Izadpanah

  4. Departments of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA

    Asim B. Abdel-Mageed

  5. Division of Plastic and Reconstructive Surgery, Louisiana State University, New Orleans, LA, USA

    Charles L. Dupin

  6. Department of Biostatistics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA

    Sudesh K. Srivastav

  7. Isar Medical Center, Department of Medicine, Interdisciplinary Stem Cell Laboratory, Munich, Germany

    Eckhard U. Alt

  8. Heart and Vascular Institute, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-48, Room 9520, New Orleans, LA, 70112, USA

    Reza Izadpanah

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  1. Christiane Senst
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Corresponding author

Correspondence to Reza Izadpanah.

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Christiane Senst and Timo Nazari-Shafti have contributed equally to this study.

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Fig. S1

B-ASC and A-ASC characteristics. A) Differentiation potential of A-ASCs and B-ASCs: adipogenic potentials of A-ASC and B-ASCs was shown by staining differentiated cells with Oil Red O following 14 days incubation in adipogenic differentiation media (I&II). Osteogenic potentials of A-ASCs and B-ASCs were examined by incubation of cells in osteogenic media for 12 days, and then cells were stained with Alizarin red (III&IV). Both ASC types promoted the formation of chondrocytes when they were incubated in chondrogenic media for 21 days. Spheres then embedded in paraffin and stained with toluidin blue (slices of 10 μm) (V&VI). B. Box plots of invasion assay in 6 h and 24 h in MDA-CM, B. Invasion in MCF-CM. Left box plot non-migrated subpopulation, right box plots migrated subpopulation in each figure. Top row shows the fraction of cells migrated within 6 h and bottom row display the migration following 24 h of incubation cells in contact with condition media (P < 0.05) (PDF 129 kb)

Fig. S2

Histology of tumor and adipose tissues collected from AS and IDC breast cancers. Hematoxylin and Eosin staining of tumor and adipose tissues. The adipose tissues were harvested from 5 cm distance of the tumor tissues (PDF 588 kb)

Fig. S3

Flow cytometry analysis: B-ASCs, ASCIDC and ASCAS were profiled for the cell surface markers. Gray Filled = Isotype, Gray Line = B-ASCs, Black Line = Migrated Subpopulation, Black Dots = Non-Migrated Subpopulations (PDF 73 kb)

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Senst, C., Nazari-Shafti, T., Kruger, S. et al. Prospective dual role of mesenchymal stem cells in breast tumor microenvironment. Breast Cancer Res Treat 137, 69–79 (2013). https://doi.org/10.1007/s10549-012-2321-0

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  • DOI: https://doi.org/10.1007/s10549-012-2321-0

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