ArticleOncogene2020
Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.
- Prognostic Value of Podoplanin in Various Tumors.Technology in cancer research & treatmentPooled it
- Breast cancer cell-derived adrenomedullin confers cancer-associated adipose remodeling through the cAMP/Creb1/Zeb1 axis.British journal of cancer · 2025Article
- Adipocyte-specific Zeb1 downregulation remodels the tumor-associated adipose microenvironment to facilitate female breast cancer progression.Nature communications · 2025Article
- Alterations of the microenvironment of hepatocellular carcinoma in different unfolded protein response activity states.Discover oncology · 2025Article
- WGCNA reveals a biomarker for cancer-associated fibroblasts to predict prognosis in cervical cancer.Journal of the Chinese Medical Association : JCMA · 2024Article
- Mediator kinase inhibition reverses castration resistance of advanced prostate cancer.The Journal of clinical investigation · 2024Article
- Article
- Identification and Validation of a Prognostic Signature Derived from the Cancer Stem Cells for Oral Squamous Cell Carcinoma.International journal of molecular sciences · 2024Article
- Article
- Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families.Cancers · 2023Review
- Machine learning-based prognostic modeling of lysosome-related genes for predicting prognosis and immune status of patients with hepatocellular carcinoma.Frontiers in immunology · 2023Article
- Review
- Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure-Activity Relationships and Optimization.Journal of medicinal chemistry · 2021Article
- Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin.Frontiers in cell and developmental biology · 2021Review
- Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor.ACS pharmacology & translational science · 2020Article
- Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy.Frontiers in oncology · 2020Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor metastasis is a primary source of morbidity and mortality in cancer. Adrenomedullin (AM) is a multifunctional peptide regulated by receptor activity-modifying proteins (RAMPs). We previously reported that the AM-RAMP2 system is involved in tumor angiogenesis, but the function of the AM-RAMP3 system remains largely unknown. Here, we investigated the actions of the AM-RAMP2 and 3 systems in the tumor microenvironment and their impact on metastasis. PAN02 pancreatic cancer cells were injected into the spleens of mice, leading to spontaneous liver metastasis. Tumor metastasis was enhanced in vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-). By contrast, metastasis was suppressed in RAMP3-/- mice, where the number of podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) was reduced in the periphery of tumors at metastatic sites. Because PDPN-positive CAFs are a hallmark of tumor malignancy, we assessed the regulation of PDPN and found that Src/Cas/PDPN signaling is mediated by RAMP3. In fact, RAMP3 deficiency CAFs suppressed migration, proliferation, and metastasis in co-cultures with tumor cells in vitro and in vivo. Moreover, the activation of RAMP2 in RAMP3-/- mice suppressed both tumor growth and metastasis. Based on these results, we suggest that the upregulation of PDPN in DI-E-RAMP2-/- mice increases malignancy, while the downregulation of PDPN in RAMP3-/- mice reduces it. Selective activation of RAMP2 and inhibition of RAMP3 would therefore be expected to suppress tumor metastasis. This study provides the first evidence that understanding and targeting to AM-RAMP systems could contribute to the development of novel therapeutics against metastasis.
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