The peritoneal tumour microenvironment of high-grade serous ovarian cancer.
High-grade serous ovarian cancer (HGSC) disseminates early and extensively throughout the peritoneal space, causing multiple lesions that are a major clinical problem. The aim of this study was to investigate the cellular composition of peritoneal tumour deposits in patient biopsies and their evolution in mouse models using immunohistochemistry, intravital microscopy, confocal microscopy, and 3D modelling. Tumour deposits from the omentum of HGSC patients contained a prominent leukocyte infiltrate of CD3(+) T cells and CD68(+) macrophages, with occasional neutrophils. Alpha-smooth muscle actin(+) (α-SMA(+) ) pericytes and/or fibroblasts surrounded these well-vascularized tumour deposits. Using the murine bowel mesentery as an accessible mouse peritoneal tissue that could be easily imaged, and two different transplantable models, we found multiple microscopic tumour deposits after i.p. injection of malignant cells. Attachment to the peritoneal surface was rapid (6-48 h) with an extensive CD45(+) leukocyte infiltrate visible by 48 h. This infiltrate persisted until end point and in the syngeneic murine ID8 model, it primarily consisted of CD3(+) T lymphocytes and CD68(+) macrophages with α-SMA(+) cells also involved from the earliest stages. A majority of tumour deposits developed above existing mesenteric blood vessels, but in avascular spaces new blood vessels tracked towards the tumour deposits by 2-3 weeks in the IGROV-1 xenografts and 6 weeks in the ID8 syngeneic model; a vigorous convoluted blood supply was established by end point. Inhibition of tumour cell cytokine production by stable expression of shRNA to CXCR4 in IGROV-1 cells did not influence the attachment of cells to the mesentery but delayed neovascularization and reduced tumour deposit size. We conclude that the multiple peritoneal tumour deposits found in HGSC patients can be modelled in the mouse. The techniques described here may be useful for assessing treatments that target the disseminated stage of this disease.
Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M6BQ, UK.
D Andrew
DA
Leinster
Hagen
H
Kulbe
Gemma
G
Everitt
Richard
R
Thompson
Mauro
M
Perretti
Felicity N E
FN
Gavins
Dianne
D
Cooper
David
D
Gould
Darren P
DP
Ennis
Michelle
M
Lockley
Iain A
IA
McNeish
Sussan
S
Nourshargh
Frances R
FR
Balkwill
D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001706:Biopsy; D017252:CD3 Complex / Q000378:metabolism; D000071178:CD48 Antigen; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018613:Microscopy, Confocal; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D000097382:CD68 Molecule
D000199:Actins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D000071178:CD48 Antigen; D019718:Receptors, CXCR4; C541116:ACTA2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C527276:CXCR4 protein, human