Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy
Antiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/19/4675 |
| _version_ | 1797480306157027328 |
|---|---|
| author | Lijun Tan Katelyn Tondo-Steele Caroline Foster Carrie McIlwain Danielle E. Bolland Howard C. Crawford Andrew Sciallis Karen McLean |
| author_facet | Lijun Tan Katelyn Tondo-Steele Caroline Foster Carrie McIlwain Danielle E. Bolland Howard C. Crawford Andrew Sciallis Karen McLean |
| author_sort | Lijun Tan |
| collection | DOAJ |
| description | Antiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce tumor cell JAK-STAT signaling to promote cancer growth. Crosstalk between estrogen signaling and cytokine signaling has been reported. Therefore, we sought to characterize the impact of IL6/LIF signaling on estrogen signaling in epithelial ovarian cancer and investigate the efficacy of combination therapy. We first assessed patient tumors for cytokine expression and compared it with response to AET to determine clinical relevance. In vitro, we determined the effect of IL6/LIF on estrogen receptor expression and signaling. Cell viability assays were used to determine the efficacy and potential synergy of cytokine blockade and AET. We then extended studies to animal models, incorporating patient-derived stromal cells. Our results demonstrated shorter progression-free interval on AET in patients with stromal IL6/LIF expression. In vitro, IL6/LIF increased tumor cell estrogen receptor expression and signaling, and combination cytokine blockade and AET resulted in synergistic inhibition of tumor cell growth. The anticancer effect was verified in a mouse model. In conclusion, due to crosstalk between IL6/LIF cytokine signaling and estrogen signaling, dual blockade is a potential new treatment approach for ovarian cancer. |
| first_indexed | 2024-03-09T21:58:05Z |
| format | Article |
| id | doaj.art-d5eca5c87b274408a21398e310e91040 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:58:05Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d5eca5c87b274408a21398e310e910402023-11-23T19:54:44ZengMDPI AGCancers2072-66942022-09-011419467510.3390/cancers14194675Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen TherapyLijun Tan0Katelyn Tondo-Steele1Caroline Foster2Carrie McIlwain3Danielle E. Bolland4Howard C. Crawford5Andrew Sciallis6Karen McLean7Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, USADivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, USADivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, USACancer Institute of Chicago, 6700 West 95th Street, Suite 330, Oak Lawn, IL 60453, USAScience and Math Division, University of Minnesota, 600 East 4th Street, Morris, MN 56267, USAHenry Ford Pancreatic Cancer Center, Henry Ford Hospital, 2799 W. Grand Blvd, Detroit, MI 48202, USAPathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USADivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, USAAntiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce tumor cell JAK-STAT signaling to promote cancer growth. Crosstalk between estrogen signaling and cytokine signaling has been reported. Therefore, we sought to characterize the impact of IL6/LIF signaling on estrogen signaling in epithelial ovarian cancer and investigate the efficacy of combination therapy. We first assessed patient tumors for cytokine expression and compared it with response to AET to determine clinical relevance. In vitro, we determined the effect of IL6/LIF on estrogen receptor expression and signaling. Cell viability assays were used to determine the efficacy and potential synergy of cytokine blockade and AET. We then extended studies to animal models, incorporating patient-derived stromal cells. Our results demonstrated shorter progression-free interval on AET in patients with stromal IL6/LIF expression. In vitro, IL6/LIF increased tumor cell estrogen receptor expression and signaling, and combination cytokine blockade and AET resulted in synergistic inhibition of tumor cell growth. The anticancer effect was verified in a mouse model. In conclusion, due to crosstalk between IL6/LIF cytokine signaling and estrogen signaling, dual blockade is a potential new treatment approach for ovarian cancer.https://www.mdpi.com/2072-6694/14/19/4675mesenchymal stem cellsovarian cancerleukemia inhibitory factor (LIF)interleukin-6 (IL6)STAT3JAK2 inhibition |
| spellingShingle | Lijun Tan Katelyn Tondo-Steele Caroline Foster Carrie McIlwain Danielle E. Bolland Howard C. Crawford Andrew Sciallis Karen McLean Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy Cancers mesenchymal stem cells ovarian cancer leukemia inhibitory factor (LIF) interleukin-6 (IL6) STAT3 JAK2 inhibition |
| title | Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy |
| title_full | Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy |
| title_fullStr | Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy |
| title_full_unstemmed | Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy |
| title_short | Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy |
| title_sort | inhibition of tumor microenvironment cytokine signaling sensitizes ovarian cancer cells to antiestrogen therapy |
| topic | mesenchymal stem cells ovarian cancer leukemia inhibitory factor (LIF) interleukin-6 (IL6) STAT3 JAK2 inhibition |
| url | https://www.mdpi.com/2072-6694/14/19/4675 |
| work_keys_str_mv | AT lijuntan inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT katelyntondosteele inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT carolinefoster inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT carriemcilwain inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT danielleebolland inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT howardccrawford inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT andrewsciallis inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy AT karenmclean inhibitionoftumormicroenvironmentcytokinesignalingsensitizesovariancancercellstoantiestrogentherapy |