title: Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix-Directed Spheroid Formation.
abstract: Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy.
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan. Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kasagi
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Harada
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan. Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Morodomi
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan. Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Iwai
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Saito
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saeki
authors.affiliation: Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kippei
authors.initials: K
authors.lastname: Ohgaki
authors.affiliation: Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugiyama
authors.affiliation: Department of Pathology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Onimaru
authors.affiliation: Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Kyushu University Graduate School of Pharmaceutical Sciences, Fukuoka 812-8582, Japan. yonemitu@med.kyushu-u.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D016329:Sp1 Transcription Factor