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Cancers
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Tumor Microenvironment and Breast Cancer Progression
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Tumor Microenvironment and Breast Cancer Progression

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 20570

Special Issue Editor

Prof. Dr. Andreas Hartkopf

E-Mail Website
Guest Editor
Department of Gynecology and Obstetrics, University Hospital Tübingen, Tübingen, Germany
Interests: angiogenesis; immune-escape; epithelial-mesenchymal transition; drug resistance; tumor growth; tumor-cell dissemination; tumor-cell-dormancy and metastatic spread

Special Issue Information

The tumor microenvironment is closely linked to breast cancer progression, and the interaction of tumor cells with its environment plays a key role in angiogenesis, immune-escape, epithelial–mesenchymal transition, drug resistance, tumor growth, tumor-cell dissemination, tumor-cell dormancy, and metastatic spread. In this Special Issue, we focus not only on the biological role of the tumor microenvironment on breast cancer development and progression but also on new therapeutic approaches that specifically target the interaction between tumor-cells and its environment or the microenvironment itself. Moreover, we are also interested in prognostic and predictive markers that involve the tumor-microenviroment.

Prof. Dr. Andreas Hartkopf
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • angiogenesis
  • immune-escape
  • epithelial-mesenchymal transition
  • drug resistance
  • tumor growth
  • tumor-cell dissemination
  • tumor-cell-dormancy and metastatic spread

Published Papers (7 papers)

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Research

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19 pages, 2791 KiB  
Article
Possible Metastatic Stage-Dependent ILC2 Activation Induces Differential Functions of MDSCs through IL-13/IL-13Rα1 Signaling during the Progression of Breast Cancer Lung Metastasis
by Atsushi Ito, Yuichi Akama, Naoko Satoh-Takayama, Kanako Saito, Takuma Kato, Eiji Kawamoto, Arong Gaowa, Eun Jeong Park, Motoshi Takao and Motomu Shimaoka
Cancers 2022, 14(13), 3267; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133267 - 04 Jul 2022
Cited by 7 | Viewed by 2227
Abstract
Breast cancer is the most common cancer in women worldwide, and lung metastasis is one of the most frequent distant metastases. When breast cancer metastasizes to the lung, group 2 innate lymphoid cells (ILC2s) are thought to promote tumor growth via the activation [...] Read more.
Breast cancer is the most common cancer in women worldwide, and lung metastasis is one of the most frequent distant metastases. When breast cancer metastasizes to the lung, group 2 innate lymphoid cells (ILC2s) are thought to promote tumor growth via the activation of myeloid-derived suppressor cells (MDSCs), which are known to negatively regulate anticancer immune responses. However, it remains to be elucidated exactly how this ILC2–MDSC interaction is involved in tumor growth during metastases formation. Using a 4T1/LM4 breast cancer mouse model, we found that ILC2s were activated in both the micro- and macrometastatic regions, suggesting sustained activation throughout the metastatic cascades via IL-33/ST2 signaling. Consistent with IL-13 secretion from activated ILC2s, the frequencies of polymorphonuclear (PMN)- and monocytic (M)-MDSCs were also significantly elevated during the progression from micro- to macrometastatic cancer. However, the effects of ILC2-induced MDSC functionality on the microenvironment differed in a metastatic-stage-specific manner. Our findings indicate that ILC2s may induce the immunosuppressive functions of MDSCs during the later stages of metastasis. Concomitantly, ILC2 may instigate extracellular matrix remodeling by PMN-MDSC activation during the early stages of metastasis. These metastatic-stage-specific changes may contribute to metastatic tumor growth in the microenvironment of breast cancer lung metastasis. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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17 pages, 2384 KiB  
Article
Second-Harmonic Generation Imaging Reveals Changes in Breast Tumor Collagen Induced by Neoadjuvant Chemotherapy
by Danielle E. Desa, Wencheng Wu, Robert M. Brown, Edward B. Brown IV, Robert L. Hill, Bradley M. Turner and Edward B. Brown III
Cancers 2022, 14(4), 857; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040857 - 09 Feb 2022
Cited by 1 | Viewed by 1910
Abstract
Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects, [...] Read more.
Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects, including the increased appearance of the ‘tumor microenvironment of metastasis’, image-based multicellular signatures that are prognostic of breast tumor metastasis. To assess whether NACT can induce changes in two other image-based prognostic/predictive signatures derived from tumor collagen, we quantified second-harmonic generation (SHG) directionality and fiber alignment in formalin-fixed, paraffin-embedded sections of core needle biopsies and primary tumor excisions from 22 human epidermal growth factor receptor 2-overexpressing (HER2+) and 22 triple-negative breast cancers. In both subtypes, we found that SHG directionality (i.e., the forward-to-backward scattering ratio, or F/B) is increased by NACT in the bulk of the tumor, but not the adjacent tumor-stroma interface. Overall collagen fiber alignment is increased by NACT in triple-negative but not HER2+ breast tumors. These results suggest that NACT impacts the collagenous extracellular matrix in a complex and subtype-specific manner, with some prognostic features being unchanged while others are altered in a manner suggestive of a more metastatic phenotype. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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22 pages, 4692 KiB  
Article
Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines
by Kosar Jabbari, Garrett Winkelmaier, Cody Andersen, Paul Yaswen, David Quilici, Saori Furuta, Qingsu Cheng and Bahram Parvin
Cancers 2021, 13(18), 4521; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184521 - 08 Sep 2021
Cited by 9 | Viewed by 3146
Abstract
Reprogramming the tumor stroma is an emerging approach to circumventing the challenges of conventional cancer therapies. This strategy, however, is hampered by the lack of a specific molecular target. We previously reported that stromal fibroblasts (FBs) with high expression of CD36 could be [...] Read more.
Reprogramming the tumor stroma is an emerging approach to circumventing the challenges of conventional cancer therapies. This strategy, however, is hampered by the lack of a specific molecular target. We previously reported that stromal fibroblasts (FBs) with high expression of CD36 could be utilized for this purpose. These studies are now expanded to identify the secreted factors responsible for tumor suppression. Methodologies included 3D colonies, fluorescent microscopy coupled with quantitative techniques, proteomics profiling, and bioinformatics analysis. The results indicated that the conditioned medium (CM) of the CD36+ FBs caused growth suppression via apoptosis in the triple-negative cell lines of MDA-MB-231, BT549, and Hs578T, but not in the ERBB2+ SKBR3. Following the proteomics and bioinformatic analysis of the CM of CD36+ versus CD36− FBs, we determined KLF10 as one of the transcription factors responsible for growth suppression. We also identified FBLN1, SLIT3, and PENK as active ligands, where their minimum effective concentrations were determined. Finally, in MDA-MB-231, we showed that a mixture of FBLN1, SLIT3, and PENK could induce an amount of growth suppression similar to the CM of CD36+ FBs. In conclusion, our findings suggest that these ligands, secreted by CD36+ FBs, can be targeted for breast cancer treatment. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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20 pages, 3139 KiB  
Article
Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment
by Shipra Gandhi, Masanori Oshi, Vijayashree Murthy, Elizabeth A. Repasky and Kazuaki Takabe
Cancers 2021, 13(11), 2559; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112559 - 23 May 2021
Cited by 21 | Viewed by 3734
Abstract
Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). [...] Read more.
Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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Review

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24 pages, 1868 KiB  
Review
Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy
by Chenghui Wu, Shuwen Dong, Renhong Huang and Xiaosong Chen
Cancers 2023, 15(3), 726; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030726 - 24 Jan 2023
Cited by 5 | Viewed by 2437
Abstract
Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes [...] Read more.
Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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14 pages, 838 KiB  
Review
Recent Advances in the Aging Microenvironment of Breast Cancer
by Xiaocong Jiang, Haixing Shen, Xi Shang, Jianwen Fang, Yuexin Lu, Yue Lu, Jingyan Zheng and Peifen Fu
Cancers 2022, 14(20), 4990; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14204990 - 12 Oct 2022
Cited by 1 | Viewed by 2065
Abstract
Aging is one of the risk factors for advanced breast cancer. With the increasing trend toward population aging, it is important to study the effects of aging on breast cancer in depth. Cellular senescence and changes in the aging microenvironment in vivo are [...] Read more.
Aging is one of the risk factors for advanced breast cancer. With the increasing trend toward population aging, it is important to study the effects of aging on breast cancer in depth. Cellular senescence and changes in the aging microenvironment in vivo are the basis for body aging and death. In this review, we focus on the influence of the aging microenvironment on breast cancer. Increased breast extracellular matrix stiffness in the aging breast extracellular matrix can promote the invasion of breast cancer cells. The role of senescence-associated secretory phenotypes (SASPs) such as interleukin-6 (IL-6), IL-8, and matrix metalloproteases (MMPs), in breast cancer cell proliferation, invasion, and metastasis is worthy of exploration. Furthermore, the impact of senescent fibroblasts, adipocytes, and endothelial cells on the mammary matrix is discussed in detail. We also list potential targets for senotherapeutics and senescence-inducing agents in the aging microenvironment of breast cancer. In conclusion, this review offers an overview of the influence of the aging microenvironment on breast cancer initiation and progression, with the aim of providing some directions for future research on the aging microenvironment in breast cancer. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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24 pages, 1790 KiB  
Review
Transcriptional Factor Repertoire of Breast Cancer in 3D Cell Culture Models
by Hande Özkan, Deniz Gülfem Öztürk and Gozde Korkmaz
Cancers 2022, 14(4), 1023; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14041023 - 17 Feb 2022
Cited by 9 | Viewed by 3957
Abstract
Intratumor heterogeneity of breast cancer is driven by extrinsic factors from the tumor microenvironment (TME) as well as tumor cell–intrinsic parameters including genetic, epigenetic, and transcriptomic traits. The extracellular matrix (ECM), a major structural component of the TME, impacts every stage of tumorigenesis [...] Read more.
Intratumor heterogeneity of breast cancer is driven by extrinsic factors from the tumor microenvironment (TME) as well as tumor cell–intrinsic parameters including genetic, epigenetic, and transcriptomic traits. The extracellular matrix (ECM), a major structural component of the TME, impacts every stage of tumorigenesis by providing necessary biochemical and biomechanical cues that are major regulators of cell shape/architecture, stiffness, cell proliferation, survival, invasion, and migration. Moreover, ECM and tissue architecture have a profound impact on chromatin structure, thereby altering gene expression. Considering the significant contribution of ECM to cellular behavior, a large body of work underlined that traditional two-dimensional (2D) cultures depriving cell–cell and cell–ECM interactions as well as spatial cellular distribution and organization of solid tumors fail to recapitulate in vivo properties of tumor cells residing in the complex TME. Thus, three-dimensional (3D) culture models are increasingly employed in cancer research, as these culture systems better mimic the physiological microenvironment and shape the cellular responses according to the microenvironmental cues that will regulate critical cell functions such as cell shape/architecture, survival, proliferation, differentiation, and drug response as well as gene expression. Therefore, 3D cell culture models that better resemble the patient transcriptome are critical in defining physiologically relevant transcriptional changes. This review will present the transcriptional factor (TF) repertoire of breast cancer in 3D culture models in the context of mammary tissue architecture, epithelial-to-mesenchymal transition and metastasis, cell death mechanisms, cancer therapy resistance and differential drug response, and stemness and will discuss the impact of culture dimensionality on breast cancer research. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Breast Cancer Progression)
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