title: A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment.
abstract: Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERα and ERβ, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERα and ERβ transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface.
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Ellem
authors.forename: Renea A
authors.initials: RA
authors.lastname: Taylor
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Mark
authors.initials: M
authors.lastname: Frydenberg
authors.forename: David
authors.initials: D
authors.lastname: Pook
authors.forename: John
authors.initials: J
authors.lastname: Pedersen
authors.forename: Bree
authors.initials: B
authors.lastname: Cawsey
authors.forename: Andrew
authors.initials: A
authors.lastname: Trotta
authors.forename: Eleanor
authors.initials: E
authors.lastname: Need
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
mesh_terms: D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D016207:Cytokines; D004967:Estrogens; D019718:Receptors, CXCR4; D011960:Receptors, Estrogen
keywords: CXCL12; mast cells; microenvironment; oestrogen; prostate; stroma