Targeting the Tumor Microenvironment: JAK-STAT3 Signaling

Overview

Journal JAKSTAT

Date 2013 Sep 24

PMID 24058812

Citations 105

Authors

Eirini Bournazou

Jacqueline Bromberg

Affiliations

Soon will be listed here.

Abstract

Persistent JAK-STAT3 signaling is implicated in many aspects of tumorigenesis. Apart from its tumor-intrinsic effects, STAT3 also exerts tumor-extrinsic effects, supporting tumor survival and metastasis. These involve the regulation of paracrine cytokine signaling, alterations in metastatic sites rendering these permissive for the growth of cancer cells and subversion of host immune responses to create an immunosuppressive environment. Targeting this signaling pathway is considered a novel promising therapeutic approach, especially in the context of tumor immunity. In this article, we will review to what extent JAK-STAT3-targeted therapies affect the tumor microenvironment and whether the observed effects underlie responsiveness to therapy.

Citing Articles

Identification of hub genes and immune-related pathways in acute myeloid leukemia: insights from bioinformatics and experimental validation.

Shan M, Xu L, Yang W, Liu S, Cui Z Front Immunol. 2025; 15:1511824.

PMID: 39867885 PMC: 11757261. DOI: 10.3389/fimmu.2024.1511824.

Overexpression of IL-6 and STAT3 may provide new insights into ovine pulmonary adenocarcinoma development.

Toma C, Popa R, Ciobanu L, Baldea I, Amorim I, Bochynska D BMC Vet Res. 2025; 21(1):29.

PMID: 39833798 PMC: 11744984. DOI: 10.1186/s12917-024-04429-6.

Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2.

Miyazaki S, Kitazawa M, Nakamura S, Koyama M, Yamamoto Y, Hondo N Mol Oncol. 2024; 19(2):377-390.

PMID: 39400496 PMC: 11793007. DOI: 10.1002/1878-0261.13751.

STAT3 Regulates the Redox Profile in MDA-MB-231 Breast Cancer Cells.

Rodrigues J, Pires B, de Amorim I, Siqueira P, de Sousa Rodrigues M, da Fonseca A Cell Biochem Biophys. 2024; 82(4):3507-3516.

PMID: 39033092 DOI: 10.1007/s12013-024-01439-x.

Crosstalk between CXCL12/CXCR4/ACKR3 and the STAT3 Pathway.

Ma Z, Zhou F, Jin H, Wu X Cells. 2024; 13(12.

PMID: 38920657 PMC: 11201928. DOI: 10.3390/cells13121027.

References

Tsuyada A, Chow A, Wu J, Somlo G, Chu P, Loera S . CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 2012; 72(11):2768-79. PMC: 3367125. DOI: 10.1158/0008-5472.CAN-11-3567. View

Sekine Y, Tsuji S, Ikeda O, Sato N, Aoki N, Aoyama K . Regulation of STAT3-mediated signaling by LMW-DSP2. Oncogene. 2006; 25(42):5801-6. DOI: 10.1038/sj.onc.1209578. View

Yang J, Liao D, Chen C, Liu Y, Chuang T, Xiang R . Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells. 2012; 31(2):248-58. DOI: 10.1002/stem.1281. View

Bromberg J, Wang T . Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009; 15(2):79-80. PMC: 3684978. DOI: 10.1016/j.ccr.2009.01.009. View

Stark G, Darnell Jr J . The JAK-STAT pathway at twenty. Immunity. 2012; 36(4):503-14. PMC: 3909993. DOI: 10.1016/j.immuni.2012.03.013. View

Xin H, Herrmann A, Reckamp K, Zhang W, Pal S, Hedvat M . Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res. 2011; 71(21):6601-10. PMC: 3206173. DOI: 10.1158/0008-5472.CAN-11-1217. View

Walter M, Liang S, Ghosh S, Hornsby P, Li R . Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene. 2009; 28(30):2745-55. PMC: 2806057. DOI: 10.1038/onc.2009.130. View

He B, You L, Uematsu K, Zang K, Xu Z, Lee A . SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A. 2003; 100(24):14133-8. PMC: 283558. DOI: 10.1073/pnas.2232790100. View

Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H . Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008; 118(10):3367-77. PMC: 2528912. DOI: 10.1172/JCI35213. View

10.

Fukuda A, Wang S, Morris 4th J, Folias A, Liou A, Kim G . Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011; 19(4):441-55. PMC: 3075548. DOI: 10.1016/j.ccr.2011.03.002. View

11.

Guo Y, Xu F, Lu T, Duan Z, Zhang Z . Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012; 38(7):904-10. DOI: 10.1016/j.ctrv.2012.04.007. View

12.

Hedvat M, Huszar D, Herrmann A, Gozgit J, Schroeder A, Sheehy A . The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009; 16(6):487-97. PMC: 2812011. DOI: 10.1016/j.ccr.2009.10.015. View

13.

Studebaker A, Storci G, Werbeck J, Sansone P, Sasser A, Tavolari S . Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res. 2008; 68(21):9087-95. DOI: 10.1158/0008-5472.CAN-08-0400. View

14.

Greten F, Karin M . Peering into the aftermath: JAKi rips STAT3 in cancer. Nat Med. 2010; 16(10):1085-7. DOI: 10.1038/nm1010-1085. View

15.

Langowski J, Zhang X, Wu L, Mattson J, Chen T, Smith K . IL-23 promotes tumour incidence and growth. Nature. 2006; 442(7101):461-5. DOI: 10.1038/nature04808. View

16.

de Groot J, Liang J, Kong L, Wei J, Piao Y, Fuller G . Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma. Oncotarget. 2012; 3(9):1036-48. PMC: 3660053. DOI: 10.18632/oncotarget.663. View

17.

Nefedova Y, Cheng P, Gilkes D, Blaskovich M, Beg A, Sebti S . Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J Immunol. 2005; 175(7):4338-46. PMC: 1351251. DOI: 10.4049/jimmunol.175.7.4338. View

18.

Schafer Z, Brugge J . IL-6 involvement in epithelial cancers. J Clin Invest. 2007; 117(12):3660-3. PMC: 2096452. DOI: 10.1172/JCI34237. View

19.

Tebbutt N, Giraud A, Inglese M, Jenkins B, Waring P, Clay F . Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med. 2002; 8(10):1089-97. DOI: 10.1038/nm763. View

20.

Wang L, Yi T, Kortylewski M, Pardoll D, Zeng D, Yu H . IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009; 206(7):1457-64. PMC: 2715087. DOI: 10.1084/jem.20090207. View