RGD Reference Report - Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts. - Rat Genome Database

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Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts.

Authors: Dai, Kun  Tanaka, Megumu  Kamiyoshi, Akiko  Sakurai, Takayuki  Ichikawa-Shindo, Yuka  Kawate, Hisaka  Cui, Nanqi  Wei, Yangxuan  Tanaka, Masaaki  Kakihara, Shinji  Matsui, Shuhei  Shindo, Takayuki 
Citation: Dai K, etal., Oncogene. 2020 Feb;39(9):1914-1930. doi: 10.1038/s41388-019-1112-z. Epub 2019 Nov 21.
RGD ID: 152985691
Pubmed: PMID:31754214   (View Abstract at PubMed)
DOI: DOI:10.1038/s41388-019-1112-z   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RAMP2HumanNeoplasm Metastasis  ISORamp2 (Mus musculus) RGD 
Ramp2RatNeoplasm Metastasis  ISORamp2 (Mus musculus) RGD 
Ramp2MouseNeoplasm Metastasis  IMP  RGD 
RAMP2Humanspleen cancer amelioratesISORamp2 (Mus musculus) RGD 
Ramp2Ratspleen cancer amelioratesISORamp2 (Mus musculus) RGD 
Ramp2Mousespleen cancer amelioratesIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ramp2  (receptor activity modifying protein 2)

Genes (Mus musculus)
Ramp2  (receptor (calcitonin) activity modifying protein 2)

Genes (Homo sapiens)
RAMP2  (receptor activity modifying protein 2)

Additional Information