# Metastatic organotropism in peritoneal metastasis: Paget’s hypothesis revisited **Authors:** Dongchan Kim, Devesh Kaushal, Robert Beaumont Wilson PMC · DOI: 10.1007/s10238-025-01868-9 · 2026-01-29 ## TL;DR This paper explores how cancer spreads to the peritoneum through exosomes, supporting Paget’s seed and soil hypothesis. ## Contribution The study highlights the role of exosomes in preparing the peritoneal environment for metastasis and identifies specific cancer subtypes involved. ## Key findings - Exosomes facilitate peritoneal metastasis by degrading the glycocalyx and transforming mesothelial cells. - Mesenchymal cancer subtypes show a higher tendency for peritoneal metastasis. - Exosomes contribute to immunosuppression and ascites in the peritoneal environment. ## Abstract Peritoneal metastasis (PM) of solid tumours is a major contributor to cancer-associated mortality and morbidity. The mechanism of PM development encapsulates Paget’s hypothesis of seed and soil, whereby cancer cells remotely prepare a pre-metastatic niche in the peritoneal microenvironment to facilitate transcoelomic cancer progression. The bidirectional communication between cancer cells and host mesothelial cells, endothelial cells, leukocytes, adipocytes, and fibroblasts occurs via exosomes. Exosomes are nano-sized extracellular vesicles that carry cargos of proteins, cytokines, and microRNA. Cancer-derived exosomes enable exfoliated tumour cells to resist anoikis, disseminate, adhere, and implant in the peritoneum. This process involves the degradation of the peritoneal glycocalyx, the transformation of peritoneal mesothelial cells into cancer-associated fibroblasts via mesothelial-mesenchymal transition, and metabolic coupling with omental and subperitoneal adipocytes. Exosomes also enhance ascites and peritoneal immunosuppression. Exosomes promote PM development from mesenchymal subtypes of epithelial cancers, which have a predilection for transcoelomic metastasis compared to other molecular subtypes. Mesenchymal subtypes include diffuse gastric cancer, CMS4 colorectal cancer, and high-grade serous ovarian carcinoma. Understanding the oncogenic roles of exosomal cargo offers potential for future research and therapy in PM. ## Linked entities - **Diseases:** diffuse gastric cancer (MONDO:0007648), colorectal cancer (MONDO:0005575) ## Full-text entities - **Genes:** TRAF6 (TNF receptor associated factor 6) [NCBI Gene 7189] {aka MGC:3310, RNF85}, CXCL12 (C-X-C motif chemokine ligand 12) [NCBI Gene 6387] {aka IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1}, TAF1 (TATA-box binding protein associated factor 1) [NCBI Gene 6872] {aka BA2R, CCG1, CCGS, DYT3, DYT3/TAF1, KAT4}, NOP16 (NOP16 nucleolar protein) [NCBI Gene 51491] {aka HSPC111, HSPC185}, COPS5 (COP9 signalosome subunit 5) [NCBI Gene 10987] {aka CSN5, JAB1, MOV-34, SGN5}, HLA-C (major histocompatibility complex, class I, C) [NCBI Gene 3107] {aka D6S204, HLA-JY3, HLAC, HLC-C, MHC, PSORS1}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, CDK4 (cyclin dependent kinase 4) [NCBI Gene 1019] {aka CMM3, MCPH31, PSK-J3}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, TSG101 (tumor susceptibility 101) [NCBI Gene 7251] {aka TSG10, VPS23}, CCL25 (C-C motif chemokine ligand 25) [NCBI Gene 6370] {aka Ck beta-15, Ckb15, SCYA25, TECK, TECKvar}, HAS1 (hyaluronan synthase 1) [NCBI Gene 3036] {aka HAS}, NUP62 (nucleoporin 62) [NCBI Gene 23636] {aka IBSN, SNDI, p62}, CXCR2 (C-X-C motif chemokine receptor 2) [NCBI Gene 3579] {aka CD182, CDw128b, CMKAR2, IL8R2, IL8RA, IL8RB}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, CD81 (CD81 molecule) [NCBI Gene 975] {aka CVID6, S5.7, TAPA1, TSPAN28}, ACTR3 (actin related protein 3) [NCBI Gene 10096] {aka ARP3}, CTTN (cortactin) [NCBI Gene 2017] {aka EMS1}, TIMP2 (TIMP metallopeptidase inhibitor 2) [NCBI Gene 7077] {aka CSC-21K, DDC8}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1}, RAB27A (RAB27A, member RAS oncogene family) [NCBI Gene 5873] {aka GS2, HsT18676, RAB27, RAM}, ITGA5 (integrin subunit alpha 5) [NCBI Gene 3678] {aka CD49e, FNRA, VLA-5, VLA5A}, IRAK1 (interleukin 1 receptor associated kinase 1) [NCBI Gene 3654] {aka IRAK, pelle}, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) [NCBI Gene 3156] {aka LDLCQ3, LGMDR28, MYPLG}, MUC6 (mucin 6, oligomeric mucus/gel-forming (gene/pseudogene)) [NCBI Gene 4588] {aka MUC-6}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, RBBP4 (RB binding protein 4, chromatin remodeling factor) [NCBI Gene 5928] {aka NURF55, RBAP48, lin-53}, SMAD7 (SMAD family member 7) [NCBI Gene 4092] {aka CRCS3, MADH7, MADH8}, PXN (paxillin) [NCBI Gene 5829], HSP90AA1 (heat shock protein 90 alpha family class A member 1) [NCBI Gene 3320] {aka EL52, HEL-S-65p, HSP86, HSP89A, HSP90A, HSP90N}, CCR1 (C-C motif chemokine receptor 1) [NCBI Gene 1230] {aka CD191, CKR-1, CKR1, CMKBR1, HM145, MIP1aR}, CXCL1 (C-X-C motif chemokine ligand 1) [NCBI Gene 2919] {aka FSP, GRO1, GROa, MGSA, MGSA-a, NAP-3}, CD44 (CD44 molecule (IN blood group)) [NCBI Gene 960] {aka CDW44, CSPG8, ECM-III, ECMR-III, H-CAM, HCELL}, PDCD6IP (programmed cell death 6 interacting protein) [NCBI Gene 10015] {aka AIP1, ALIX, DRIP4, HP95, MCPH29}, PDPN (podoplanin) [NCBI Gene 10630] {aka AGGRUS, D2-40, GP36, GP40, Gp38, HT1A-1}, SNHG12 (small nucleolar RNA host gene 12) [NCBI Gene 85028] {aka ASLNC04080, C1orf79, LINC00100, LINC001000, NCRNA00100, PNAS-123}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, HPSE (heparanase) [NCBI Gene 10855] {aka HPA, HPA1, HPR1, HPSE1, HSE1}, CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, ST3GAL5 (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) [NCBI Gene 8869] {aka SATI, SIAT9, SIATGM3S, SPDRS, ST3Gal V, ST3GalV}, KDR (kinase insert domain receptor) [NCBI Gene 3791] {aka CD309, FLK1, VEGFR, VEGFR2}, VAMP7 (vesicle associated membrane protein 7) [NCBI Gene 6845] {aka SYBL1, TI-VAMP, TIVAMP, VAMP-7}, CXCL5 (C-X-C motif chemokine ligand 5) [NCBI Gene 6374] {aka ENA-78, SCYB5}, SMPD3 (sphingomyelin phosphodiesterase 3) [NCBI Gene 55512] {aka NSMASE2}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, RAB31 (RAB31, member RAS oncogene family) [NCBI Gene 11031] {aka Rab22B}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, RAB6A (RAB6A, member RAS oncogene family) [NCBI Gene 5870] {aka RAB6}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, MUC1 (mucin 1, cell surface associated) [NCBI Gene 4582] {aka ADMCKD, ADMCKD1, ADTKD2, CA 15-3, CD227, Ca15-3}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, ABCB1 (ATP binding cassette subfamily B member 1) [NCBI Gene 5243] {aka ABC20, CD243, CLCS, ENPAT, GP170, MDR1}, S100A4 (S100 calcium binding protein A4) [NCBI Gene 6275] {aka 18A2, 42A, CAPL, FSP1, MTS1, P9KA}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, ACLY (ATP citrate lyase) [NCBI Gene 47] {aka ACL, ATPCL, CLATP}, POU5F1 (POU class 5 homeobox 1) [NCBI Gene 5460] {aka OCT3, OCT4, OCT4Borf1, OTF-3, OTF3, OTF4}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53} - **Diseases:** liver metastasis (MESH:D009362), Primary peritoneal cancer (MESH:D010534), prostate cancer (MESH:D011471), aneuploidy (MESH:D000782), MSS (MESH:D013132), Hypoxia (MESH:D000860), LGL (MESH:D054066), H. pylori infection (MESH:D016481), Krukenberg tumours (MESH:D007725), ischaemia (MESH:D007511), PDAC (MESH:D021441), hyperthermia (MESH:D005334), PMC (MESH:D020967), CMS1 CRC (MESH:D015179), peritoneal seeding (MESH:D009366), NECL (MESH:C537419), Inflammatory (MESH:D007249), Epstein-Barr virus-positive (EBV+) tumours (MESH:D020031), breast cancer (MESH:D001943), EMT (MESH:D002277), HSP (MESH:D012769), Gastrointestinal malignancies (MESH:D005770), EOC (MESH:D000077216), metastatic dissemination (MESH:D000092182), pancreatic cancer (MESH:D010190), Malignant ascites (MESH:D001201), infections (MESH:D007239), mesenchymal-type solid tumours (MESH:D008637), Paget (MESH:C537701), Adenomatous polyposis coli (MESH:D011125), signet ring cell cancers (MESH:D018279), HGSOC (MESH:D010051), Cancer (MESH:D009369), PM (MESH:D010538), acidosis (MESH:D000138), sepsis (MESH:D018805), invasive (MESH:D009361), MMT (MESH:D018301), Hypoxic (MESH:D002534), Milky Spots (MESH:D008796), malignant melanoma (MESH:D008545), bladder cancer (MESH:D001749), DGC (MESH:D013274), cytotoxicity (MESH:D064420) - **Chemicals:** Indomethacin (MESH:D007213), ketotifen (MESH:D007665), simvastatin (MESH:D019821), glibenclamide (MESH:D005905), dimethyl amiloride (MESH:C039465), carbohydrate (MESH:D002241), cisplatin (MESH:D002945), oxygen (MESH:D010100), heparan sulfates (MESH:D006497), reactive oxygen species (MESH:D017382), Phosphatidylcholine (MESH:D010713), phosphatidylserine (MESH:D010718), proton (MESH:D011522), ATP (MESH:D000255), phospholipids (MESH:D010743), acetyl-coenzyme A (MESH:D000105), hyaluronan (MESH:D006820), tricarboxylic acid (MESH:D014233), celecoxib (MESH:D000068579), Dynasore (MESH:C511794), Cholesterol (MESH:D002784), Y27632 (MESH:C108830), calpeptin (MESH:C071482), GW4869 (MESH:C468773), vitamin B5 (MESH:D010205), gemcitabine (MESH:D000093542), Dasatinib (MESH:D000069439), Tipifarnib (MESH:C402769), lipid (MESH:D008055), GTP (MESH:D006160), calcium (MESH:D002118), heparin (MESH:D006493), bevacizumab (MESH:D000068258), platinum (MESH:D010984), omeprazole (MESH:D009853), imipramine (MESH:D007099), Rapamycin (MESH:D020123), genistein (MESH:D019833), maraviroc (MESH:D000077592), D-pantethine (MESH:C005425), glycolipids (MESH:D006017), manumycin A (MESH:C054474), GAG (MESH:D006025), 5E1 (-), sphingomyelin (MESH:D013109), anthracyclines (MESH:D018943), ceramide (MESH:D002518), doxorubicin (MESH:D004317), lactate (MESH:D019344), pixantrone (MESH:C086548), DMOG (MESH:C040947) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Helicobacter pylori (species) [taxon 210] - **Cell lines:** MeT-5A — Homo sapiens (Human), Transformed cell line (CVCL_3749), HT29 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0320), HMrSV5 — Mus musculus (Mouse), Transformed cell line (CVCL_5U93), CMS4 — Homo sapiens (Human), Childhood acute megakaryoblastic leukemia, Cancer cell line (CVCL_H248), PMC — Homo sapiens (Human), Finite cell line (CVCL_3773), OVCAR-3 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_0465), SKOV3 — Homo sapiens (Human), Ovarian serous cystadenocarcinoma, Cancer cell line (CVCL_0532), HCT116 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0291), DGC — Homo sapiens (Human), Gastric adenocarcinoma, Cancer cell line (CVCL_1611) ## Figures 11 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12858513/full.md --- Source: https://tomesphere.com/paper/PMC12858513