Periostin facilitates ovarian cancer recurrence by enhancing cancer stemness

Ovarian cancer (OC) is the deadliest reproductive system cancer. Its high lethality is due to the high recurrence rate and the development of chemotherapeutic resistance, which requires synergy between cancer cells and non-cancerous cells of the tumor microenvironment (TME). Analysis of gene expression microarray data from paired primary and recurrent OC tissues revealed significantly elevated expression of the gene encoding periostin (POSTN) in recurrent OC compared to matched primary tumors (p=0.014). Finding POSTN primarily localized to the TME, we investigated the role of TME POSTN in OC cell viability, migration/invasion, and chemosensitivity. Conditioned media with high levels of POSTN (CMPOSTNhigh) was generated using POSTN-transfected fibroblastic preadipocyte 3T3-L1 cells. CMPOSTNhigh-cultured OC cells exhibited faster migration, more invasiveness (p=0.006), and more chemoresistance (p<0.05) compared to OC cells cultured with control medium (CMCTL). Furthermore, CMPOSTNhigh-cultured HEYA8 cells demonstrated increased resistance to paxlitaxel-induced apoptosis. Multiple OC cell lines (HEYA8, CAOV2, and SKOV3) cultured with CMPOSTNhigh showed increases in stem cell side population relative to CMCTL-cultured cells. POSTN-transfected 3T3-L1 cells exhibited more intracellular and extracellular lipids, and this was linked to increased cancer cell expression of the oncogene fatty acid synthetase (FASN). Additionally, POSTN functions in the TME were linked to Akt pathway activities. In a xenograft mouse model of OC, the mean tumor volume in mice injected with CMPOSTNhigh-grown OC cells was larger than that in mice injected with CMCTL-grown OC cells (p=0.0023). Altogether, higher POSTN expression is present in recurrent OC and promotes a more aggressive and chemoresistant oncogenic phenotype in vitro. Within cancer TME fibroblasts, POSTN can stimulate lipid production and is associated with increased OC stem cell side population, consistent with its known role in maintaining stemness. Our results bolster the need for further study of POSTN as a potential therapeutic target in treatment and potential prevention of recurrent ovarian cancer. ### Competing Interest Statement The authors have declared no competing interest.