COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis
Menée in vitro et à l'aide d'une xénogreffe sur un modèle murin de cancer de la prostate, cette étude met en évidence un mécanisme par lequel la cyclo-oxygénase COX-2, en agissant sur la signalisation de la prolactine du stroma tumoral, favorise la tumorigenèse
The documented efficacy of COX-2 inhibitors in cancer chemoprevention and in suppression of metastasis is predominantly attributed to inflammatory responses, whereas their effects on tumor-stromal interaction are poorly understood. Through single-cell transcriptome analyses in an immune-compromised mouse xenograft model and in vitro reconstitution experiments, we uncover a tumor-stromal paracrine pathway in which secretion by tumor cells of the COX-2 product prostaglandin E2 induces prolactin production by stromal cells, which activates signaling in disseminated tumor cells with upregulated prolactin receptor expression. Analysis of multiple human cancers confirms differential tumor and stromal cell expression of COX-2, prolactin, and prolactin receptor. Together, these findings may provide novel biomarkers to inform the selective application of COX-2 inhibitors and point to additional targets for suppressing metastasis recurrence.Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.