Lymph Node Metastasis: Scavenger Receptor Mechanisms and Chemotherapy Resistance in Para-Aortic Sanctuary-Like Sites

Authors

  • Pedro Carvalho Martins Surgical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Experimental Pathology and Therapeutics Group, IPO Porto Research Center, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; RISE-Associate Laboratory (Health Research Network), Porto, Portugal; Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal; School of Medicine and Biomedical Sciences (EMCB), University Fernando Pessoa, Porto, Portugal https://orcid.org/0000-0002-1828-078X
  • Mariana Peyroteo Surgical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Experimental Pathology and Therapeutics Group, IPO Porto Research Center, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; RISE-Associate Laboratory (Health Research Network), Porto, Portugal; Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal; School of Medicine and Biomedical Sciences (EMCB), University Fernando Pessoa, Porto, Portugal https://orcid.org/0000-0002-0941-2533
  • Nuno Sousa Surgical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal https://orcid.org/0000-0001-8103-3821
  • Catarina A. Rodrigues Experimental Pathology and Therapeutics Group, IPO Porto Research Center, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; RISE-Associate Laboratory (Health Research Network), Porto, Portugal; Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal; Clinical Research Unit, IPO Porto Research Center, Portuguese Oncology Institute of Porto (IPO Porto) Porto, Portugal https://orcid.org/0000-0002-1305-8055
  • Paulo Matos Costa Faculty of Medicine of the University of Lisbon (FMUL), Lisbon, Portugal https://orcid.org/0000-0002-7550-8285
  • Lúcio Lara Santos Surgical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Experimental Pathology and Therapeutics Group, IPO Porto Research Center, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; RISE-Associate Laboratory (Health Research Network), Porto, Portugal; Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal; School of Medicine and Biomedical Sciences (EMCB), University Fernando Pessoa, Porto, Portugal https://orcid.org/0000-0002-0521-5655

DOI:

https://doi.org/10.34635/rpc.1211

Keywords:

Drug Resistance, Neoplasm, Extracellular Vesicles, Lymph Nodes, Lymphatic Metastasis, Receptors, Scavenger

Abstract

Lymph-node metastasis is a major determinant of cancer staging, prognosis and therapeutic decision-making. Rather than functioning as passive filters, tumor-draining lymph nodes are biologically active compartments that undergo vascular, stromal, and immune remodeling before and during metastatic colonization. Tumor-derived soluble mediators, extracellular vesicles, and non-coding RNAs can reach regional lymph nodes through afferent lymphatics and contribute to pre-metastatic niche formation, while stromal and myeloid populations further shape the nodal microenvironment. Within lymph-node sinuses, specialized scavenger and lectin-like receptors expressed by endothelial cells and macrophages constitute a molecular interface that may be involved in tumor-cell adhesion, retention, and immune regulation. Stabilin-1/Clever-1, Stabilin-2, LYVE-1, and MARCO are among the most relevant candidates, although the nature and strength of the supporting evidence differ between receptors. Following metastatic colonization, progressive tumor-stroma interactions may generate vascular dysfunction, increased intranodal pressure, extracellular matrix remodeling, hypoxia, immunosuppression, tumor-cell-intrinsic resistance, and dormancy, all of which may contribute to therapeutic persistence. These mechanisms are particularly relevant to para-aortic lymph-node metastases, which have been discussed as potential sanctuary sites. However, direct human evidence demonstrating systematically reduced therapeutic exposure within para-aortic metastases remains limited. This review integrates pre-metastatic nodal conditioning, scavenger receptor biology, and mechanisms of treatment resistance within a temporal model of lymph node metastatic progression and critically examines whether para-aortic nodal disease may acquire sanctuary-like behavior.

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