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Cited by 746Cancer Cells and MetastasisTGF-β signaling in diseasesAngiogenesis and VEGF in Cancer

Tumor-associated stromal cells as key contributors to the tumor microenvironment

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Bussard, Karen M., Mutkus, Lysette, Stumpf, Kristina, Gomez-Manzano, Candelaria, Marini, Frank C.·2016·Breast Cancer Research
DOI 10.1186/s13058-016-0740-2PMC PMC4982339
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Abstract

The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.

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  • Multicellular tumor spheroids are appropriate systems for modeling tumor heterogeneity and microenvironmental complexity.

    “Multicellular tumor spheroids are appropriate systems for modeling tumor heterogeneity and microenvironmental complexity [204,205,206].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [204]

    The Background describes the tumor microenvironment as heterogeneous, and its IL-6 subsection mentions tumor spheroids in a co-culture experiment. Neither passage assesses whether multicellular tumor spheroids are appropriate models of tumor heterogeneity or microenvironmental complexity. I searched for “spheroid” and for three-dimensional culture models. (LLM, conf=0.74)

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Authors
Bussard, K. M., Mutkus, L., Stumpf, K., Gomez-Manzano, C., & Marini, F. C.
Affiliations
  • Thomas Jefferson University (US)
  • Wake Forest University (US)
  • Wake Forest Baptist Comprehensive Cancer Center (US)
Corresponding author
Marini, Frank C.
ORCID
Venue
Breast Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2016-08-11
Volume
18
Issue
1
Pages
84-84
ISSN
  • 1465-5411 (ISSN-L)
  • 1465-542X
DOI
10.1186/s13058-016-0740-2
PMC
PMC4982339
OpenAlex
W2510046850
Cited by
746
References
58
Citations by year
2026: 30 · 2025: 55 · 2024: 82 · 2023: 86 · 2022: 107 · 2021: 110 · 2020: 98 · 2019: 69 · 2018: 62 · 2017: 44 · 2016: 3
FWCI
5.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Breast Cancer Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Medicine Forum (submittedVersion, cc-by)
Funders
  • National Cancer Institute (2K99CA178177)
  • National Institutes of Health (NRSA T32CA079448, 1RC1CA146381, 1R01NS069964, P50CA083639, 1R01NS09964)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
tumor stromal cells, tumor microenvironment, reactive stroma, tumor angiogenesis, tumor invasion and metastasis, treatment resistance, pericytes, adipocytes, fibroblasts, mesenchymal stem cells, matrix metalloproteinases, fibroblast activating protein, alpha-smooth muscle actin, breast cancer
MeSH terms
Cancer-Associated Fibroblasts, Breast Neoplasms, Female, Humans, Phenotype, Signal Transduction, Biomarkers, Gene Expression Regulation, Neoplastic, Stromal Cells, Adipocytes, Drug Resistance, Neoplasm, MicroRNAs, Endothelial Cells, Exosomes, Tumor Microenvironment

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