The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

Section: Immune Functionmentioning

confidence: 99%

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

Sundararajan

Sheu

et al. 2019

“…STAT3 and STAT5 are also known to be phosphorylated by several receptor tyrosine kinases (RTK), such as the ErbB family, IGF-1R, or FGFR [109], most of which are HSP90 client proteins. Interestingly, they are also activated or captured for signal transduction by those RTK without phosphorylation [110]. Given their membrane localization, these RTK must go through a complex process of folding, maturation, and membrane insertion that requires significant chaperone cooperation.…”

Section: Hsp90 and Erbb Family Of Receptor Tyrosine Kinase (Rtk)mentioning

confidence: 99%

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Hermetet

Girodon

Jego

2019

While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

“…STAT3 is part of the Signal Transducer and Activator of Transcription (STAT) family which includes seven members encoded by distinct genes. STAT3 has evolutionary conserved amino acid sequences between H. sapiens and S. harrisii (99.09%) [1]. In resting cells, STAT3 remains in an inactive form in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, STAT3 in cancer cells affects stromal cells function, establishing crosstalk between cancer cells and its microenvironment. For example STAT3 can dampen STAT1-mediated upregulation of MHC class I, allowing immune escape [1]. The other way for STAT3 to drive tumor immune escape is to regulate the function of stromal cells and more particularly immune cells.…”

Section: Introductionmentioning

confidence: 99%

STAT3, a Master Regulator of Anti-Tumor Immune Response

Rébé

Ghiringhelli

2019

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g., by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.