{
  "abstract": "Background: Cancer-associated fibroblasts (CAFs) represent a pivotal component of the breast cancer microenvironment. In a paracrine model, CAFs secreted the chemokine CXCL12 (SDF-1α), which bound to CXCR4 and activated the PI3K/AKT and MAPK signaling pathways, stimulating their migration and invasion. TGF-β1 induces myofibroblast differentiation of CAFs by acting through the TGFBR2/ALK5 receptor complex and phosphorylating SMAD2/3, thereby increasing the expression of ACTA2 and FAP. An autocrine loop has been demonstrated in CAF, whereby TGF-β1, via SMAD3, induces the transcription of CXCR4, and subsequently, CXCR4, by binding to the same cell, maintains the myofibroblast phenotype. However, a systematic comparison of paracrine and autocrine variants has not yet been conducted in the context of CAF subtypes.\n\nMethods: A secondary analysis of 101 bulk RNA-seq samples was performed, with classification into healthNF, riskNF, cancerNF, and CAF S1-S4 using correlation analysis (Spearman), differential expression (DESeq, FDR <0.05), GSEA (FDR <0.25), and a systematic review of the literature (2005–2026).\n\nResults: The PCA and the contingency table analysis enabled the description of two patterns of Cancer-associated fibroblasts subtype distribution across clinical and morphological groups: healthNF → cancerNF → CAF and healthNF → riskNF → CAF. Elevated levels of CXCR4 were identified exclusively in CAF (22.7%, FDR = 5.98 × 10−4) and were associated with the CAF-S3 and CAF-S4 fibroblast phenotypes. At CXCR4High levels, the correlation between CXCL12 and TGFB1 became negative, while the correlation between CXCL12 and ITGAV, FAP, and ITGB1 remained positive. This finding suggests a possible shift from TGF-β-dependent to CXCR4-mediated regulation of CXCL12. GSEA revealed an association of CXCR4High -CAF with enrichment of gene sets related to the interferon response, inflammation, and apoptosis, as well as with decreased enrichment of proliferation sets, EMT, and TGF-β signaling. A recent systematic review revealed that only 8.6% of publications contain experimental data supporting an autocrine loop, 17.1% describe a paracrine model, and 74.3% do not distinguish between the signaling types.\n\nConclusion: It is hypothesised that the CXCR4High-CAF transcriptome profile is compatible with a biologically plausible theory of transition between paracrine and autocrine regulatory modes and inflammatory cell states. In vitro validation is a prerequisite for establishing a causal relationship.",
  "abstract_shown": true,
  "affiliations": [
    "Scientific Center of Genetics and Life Sciences, Sirius University of Science and Technology, Sirius, Russia",
    "Meshalkin National Medical Research Center, Novosibirsk, Russia",
    "Laboratory of Biotechnology, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia"
  ],
  "article_type": "systematic review",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sergey Vladimirov"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "David Sergeevichev"
    },
    {
      "affs": [
        0
      ],
      "name": "Maria Bogachek"
    },
    {
      "affs": [
        0
      ],
      "name": "Alina Kazakova"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Anastasia Leonteva"
    },
    {
      "affs": [
        2
      ],
      "name": "Vladimir Richter"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Anna Nushtaeva"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0rra8e55kg10j.bib",
  "cited_by": 0,
  "doi": "10.3389/fbioe.2026.1920541",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13696515/",
  "id": "0rra8e55kg10j",
  "issns": [
    "2296-4185"
  ],
  "landing_url": "https://doi.org/10.3389/fbioe.2026.1920541",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Systematic Review"
    ],
    [
      "openalex",
      "2730|Chemokine receptors and signaling"
    ]
  ],
  "openalex": "W7221520130",
  "pdf_url": "https://europepmc.org/articles/PMC13696515?pdf=render",
  "pmcid": "PMC13696515",
  "pmid": "42935956",
  "published": "2026-10-12",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/0rra8e55kg10j.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:51Z",
      "native_id": "PMC13696515",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fbioe.2026.1920541"
    },
    {
      "first_seen": "2026-10-30T12:22:12Z",
      "native_id": "MED:42935956",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42935956"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Chemokine receptors and signaling",
      "subfield": "oncology"
    }
  ],
  "title": "The CXCL12/CXCR4 axis in breast cancer-associated fibroblasts: a transcriptome analysis and systematic literature review",
  "title_text": "The CXCL12/CXCR4 axis in breast cancer-associated fibroblasts: a transcriptome analysis and systematic literature review",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:33:50Z",
  "url": "https://research.draconitic.com/paper/0rra8e55kg10j",
  "venue": "Frontiers in Bioengineering and Biotechnology",
  "versions": []
}