Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors

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Abstract

There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast, and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway, activation of novel signaling such as JAK1/STAT1, and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA+ and triple-negative breast cancers, respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target.

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Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg (2011)

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

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The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism

Gerta Hoxhaj, Brendan D Manning (2019)

The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.

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CD24 signalling through macrophage Siglec-10 is a new target for cancer immunotherapy

Amira Barkal, Rachel Brewer, Maxim Markovic … (2019)

Summary: Ovarian cancer and triple-negative breast cancer (TNBC) are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. Here we show that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a new, promising target for cancer immunotherapy. Cancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic surface proteins, called “don’t eat me” signals, including CD47 1 , programmed cell death ligand 1 (PD-L1) 2 , and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M) 3 . Monoclonal antibodies which antagonize the interaction of “don’t eat me” signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers 4–5 . However, variability in the magnitude and durability of the response to these agents has suggested the presence of additional, as yet unknown, “don’t eat me” signals. Here we demonstrate a novel role for tumor-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor, Sialic Acid Binding Ig Like Lectin 10 (Siglec-10), expressed by tumor-associated macrophages (TAMs). We observe that many tumors overexpress CD24 and that TAMs express high levels of Siglec-10. Both genetic ablation of CD24 or Siglec-10, and monoclonal antibody blockade of the CD24–Siglec-10 interaction, robustly augment the phagocytosis of all CD24-expressing human tumors tested. Genetic ablation as well as therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumor growth and extension of survival, in vivo. These data highlight CD24 as a highly-expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential for CD24-blockade as cancer immunotherapy.