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Tumor Microenvironment of Breast Cancer
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Tumor Microenvironment of Breast Cancer

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

Deadline for manuscript submissions: closed (15 March 2025) | Viewed by 11703

Special Issue Editor

Dr. Masanori Oshi

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Guest Editor
1. Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
2. Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
Interests: breast cancer; tumor microenvironment; surgical oncology

Special Issue Information

Dear Colleagues,

The tumor microenvironment (TME) consists of not only cancer cells, but many other types of cells, including stromal and immune cells that play critical roles in cancer biology. The interactions that occur within the TME include fundamental mechanisms that affect tumor progression and treatment outcomes. Recently developed cancer therapeutics are targeting these interactions within the TME, including immune- and stroma-targeted approaches. The tumor immune microenvironment significantly influences patient survival, and neoadjuvant therapy with immune checkpoint inhibitors is now considered the standard of care for some triple negative breast cancers. Despite these recent advancements, many breast cancer patients still encounter resistance to treatment, progression of disease, and poor outcomes. In this Special Issue of Cancers, we hope to gather the latest findings (original articles), as well as summary reports (review articles) that discuss the breast cancer TME that will help the next generation of researchers.

Dr. Masanori Oshi
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 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.

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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

  • breast cancer
  • tumor microenvironment
  • TME
  • stromal cells

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Published Papers (5 papers)

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Research

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10 pages, 3944 KiB  
Communication
Carcinoma-Associated Fibroblasts Accelerate Growth and Invasiveness of Breast Cancer Cells in 3D Long-Term Breast Cancer Models
by Kingsley O. Osuala, Joshua Heyza, Zhiguo Zhao, Yong Xu, Kamiar Moin, Kyungmin Ji and Raymond R. Mattingly
Cancers 2024, 16(22), 3840; https://doi.org/10.3390/cancers16223840 - 15 Nov 2024
Cited by 2 | Viewed by 1447
Abstract
Background/Objectives: Carcinoma-associated fibroblasts (CAFs), a prominent cell type in the tumor microenvironment (TME), significantly contributes to cancer progression through interactions with cancer cells and other TME components. Consequently, targeting signaling pathways driven by CAFs has potential to yield new therapeutic approaches to inhibit [...] Read more.
Background/Objectives: Carcinoma-associated fibroblasts (CAFs), a prominent cell type in the tumor microenvironment (TME), significantly contributes to cancer progression through interactions with cancer cells and other TME components. Consequently, targeting signaling pathways driven by CAFs has potential to yield new therapeutic approaches to inhibit cancer progression. However, the mechanisms underlying their long-term interactions with cancer cells in vivo remains poorly understood. Methods: To address this, we developed a three-dimensional (3D) parallel coculture model of human triple-negative breast cancer (TNBC) cells and CAFs using our innovative TAME devices. This model allowed for the analysis of TNBC paracrine interactions via their secretome over extended culture periods (at least 70 days). Results: Using TNBC cell lines (MDA-MB-231, MCF10.DCIS, and HCC70), we found that TNBC spheroids in 3D parallel cocultures with CAFs exhibited more pronounced invasive finger-like outgrowths than those in cocultures of TNBC cells and normal fibroblasts (NFs) over a period of 50–70 days. We also established that the CAF-derived secretome affects TNBC migration towards the CAF secretome region. Additionally, we observed a preferential migration of CAFs, but not NFs, toward TNBC spheroids. Conclusions: Overall, our results suggest that paracrine interactions between TNBC cells and CAFs enhance TNBC invasive phenotypes and promote reciprocal migration. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Breast Cancer)
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20 pages, 3225 KiB  
Article
The Possible Role of Anti- and Protumor-Infiltrating Lymphocytes in Pathologic Complete Response in Early Breast Cancer Patients Treated with Neoadjuvant Systemic Therapy
by Klara Geršak, Blaž Matija Geršak, Barbara Gazić, Andreja Klevišar Ivančič, Primož Drev, Nina Ružić Gorenjec and Cvetka Grašič Kuhar
Cancers 2023, 15(19), 4794; https://doi.org/10.3390/cancers15194794 - 29 Sep 2023
Cited by 1 | Viewed by 1635
Abstract
The tumor microenvironment, composed of pro- and antitumor immune cells, affects cancer cell behavior. We aimed to evaluate whether tumor-infiltrating lymphocyte (TIL) density and TIL subtypes in core biopsies at the diagnosis of breast cancer patients could predict a pathologic complete response (pCR; [...] Read more.
The tumor microenvironment, composed of pro- and antitumor immune cells, affects cancer cell behavior. We aimed to evaluate whether tumor-infiltrating lymphocyte (TIL) density and TIL subtypes in core biopsies at the diagnosis of breast cancer patients could predict a pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably antitumor (CD8+, CXCL13+) and protumor (PD-1+, FOXP3+) immune cells. A prospective, noninterventional study, including 171 participants undergoing NST, was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5–23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p = 0.012, OR 1.27; 95% CI 1.05–1.54) when controlled for age (p = 0.232), Ki-67 (p = 0.001), node-negative status (p = 0.024), and HER2+/triple negative vs. luminal B-like subtype (p < 0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant and we could not make any conclusions on the direction of associations in the model with all four biomarkers. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Breast Cancer)
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12 pages, 2437 KiB  
Article
GALNT1 Expression Is Associated with Angiogenesis and Is a Prognostic Biomarker for Breast Cancer in Adolescents and Young Adults (AYA)
by Masanori Oshi, Danya Ziazadeh, Rongrong Wu, Kohei Chida, Akimitsu Yamada, Shinya Yamamoto, Kazutaka Narui, Li Yan, Takashi Ishikawa, Itaru Endo and Kazuaki Takabe
Cancers 2023, 15(13), 3489; https://doi.org/10.3390/cancers15133489 - 4 Jul 2023
Cited by 4 | Viewed by 2414
Abstract
It is well established that genetic information differs amongst the adolescent and young adult population (AYA) and older patients. Although several studies on genetic information have been conducted, no current prognostic biomarker exists to help differentiate survival outcomes amongst AYA patients. The GALNT [...] Read more.
It is well established that genetic information differs amongst the adolescent and young adult population (AYA) and older patients. Although several studies on genetic information have been conducted, no current prognostic biomarker exists to help differentiate survival outcomes amongst AYA patients. The GALNT family of genes have been associated with several cancer etiologies, such as the Tn antigen and epithelial-mesenchymal transition (EMT); however, the clinical significance of GALNT1 expression in breast cancer (BC) remains unclear. We investigated the clinical relevance of GALNT1 expression in BC using two large independent cohorts. We found that, although triple-negative BC (TNBC) had the highest GALNT1 expression compared to ER-positive/HER2-negative BC, GALNT1 levels in BC were not associated with clinical aggressiveness, including histological grade, AJCC stage and N-category, and patient survival, consistently in both the METABRIC and GSE96058 cohorts. There was also no biological difference between low- and high-GALNT1 expression BC, as analyzed by hallmark gene sets via gene set enrichment analysis (GSEA). Further, no significant difference was found in GALNT1 expression levels among AYAs and older patients. However, high GALNT1 expression was associated with significantly worse survival in AYA patients, in both cohorts. Furthermore, high GALNT1 expression was found to be an independent factor among several clinical features, including subtype, histological grade, AJCC T and N-category, in AYA patients. In both cohorts, BC with high GALNT1 expression demonstrated low levels of CD8+ T-cell infiltration, but not other anti-cancerous or pro-cancerous immune cells. Finally, high levels of GALNT1 BC demonstrated increased EMT, angiogenesis, and protein secretion in the AYA population, but not in older patients. In conclusion, our findings demonstrate that GALNT1 expression was found to be associated with angiogenesis and EMT, and may have potential as prognostic biomarker, specifically in AYA patients. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Breast Cancer)
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Review

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20 pages, 369 KiB  
Review
The Role of the Tumor Microenvironment in Triple-Positive Breast Cancer Progression and Therapeutic Resistance
by Qian Pu and Haidong Gao
Cancers 2023, 15(22), 5493; https://doi.org/10.3390/cancers15225493 - 20 Nov 2023
Cited by 4 | Viewed by 2254
Abstract
Breast cancer (BRCA) is a highly heterogeneous systemic disease. It is ranked first globally in the incidence of new cancer cases and has emerged as the primary cause of cancer-related death among females. Among the distinct subtypes of BRCA, triple-positive breast cancer (TPBC) [...] Read more.
Breast cancer (BRCA) is a highly heterogeneous systemic disease. It is ranked first globally in the incidence of new cancer cases and has emerged as the primary cause of cancer-related death among females. Among the distinct subtypes of BRCA, triple-positive breast cancer (TPBC) has been associated with increased metastasis and invasiveness, exhibiting greater resistance to endocrine therapy involving trastuzumab. It is now understood that invasion, metastasis, and treatment resistance associated with BRCA progression are not exclusively due to breast tumor cells but are from the intricate interplay between BRCA and its tumor microenvironment (TME). Accordingly, understanding the pathogenesis and evolution of the TPBC microenvironment demands a comprehensive approach. Moreover, addressing BRCA treatment necessitates a holistic consideration of the TME, bearing significant implications for identifying novel targets for anticancer interventions. This review expounds on the relationship between critical cellular components and factors in the TPBC microenvironment and the inception, advancement, and therapeutic resistance of breast cancer to provide perspectives on the latest research on TPBC. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Breast Cancer)
22 pages, 1519 KiB  
Review
Obesity and Fibrosis: Setting the Stage for Breast Cancer
by Genevra Kuziel, Brittney N. Moore and Lisa M. Arendt
Cancers 2023, 15(11), 2929; https://doi.org/10.3390/cancers15112929 - 26 May 2023
Cited by 7 | Viewed by 3088
Abstract
Obesity is a rising health concern and is linked to a worsened breast cancer prognosis. Tumor desmoplasia, which is characterized by elevated numbers of cancer-associated fibroblasts and the deposition of fibrillar collagens within the stroma, may contribute to the aggressive clinical behavior of [...] Read more.
Obesity is a rising health concern and is linked to a worsened breast cancer prognosis. Tumor desmoplasia, which is characterized by elevated numbers of cancer-associated fibroblasts and the deposition of fibrillar collagens within the stroma, may contribute to the aggressive clinical behavior of breast cancer in obesity. A major component of the breast is adipose tissue, and fibrotic changes in adipose tissue due to obesity may contribute to breast cancer development and the biology of the resulting tumors. Adipose tissue fibrosis is a consequence of obesity that has multiple sources. Adipocytes and adipose-derived stromal cells secrete extracellular matrix composed of collagen family members and matricellular proteins that are altered by obesity. Adipose tissue also becomes a site of chronic, macrophage-driven inflammation. Macrophages exist as a diverse population within obese adipose tissue and mediate the development of fibrosis through the secretion of growth factors and matricellular proteins and interactions with other stromal cells. While weight loss is recommended to resolve obesity, the long-term effects of weight loss on adipose tissue fibrosis and inflammation within breast tissue are less clear. Increased fibrosis within breast tissue may increase the risk for tumor development as well as promote characteristics associated with tumor aggressiveness. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Breast Cancer)
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