Clinical Implications and Impact of Discovery of the Thyroid Hormone Receptor on Integrin αvβ3-A Review

Abstract

Hypothyroidism has been reported to improve survival in cancer patients but only recently has the putative mechanism been identified as a receptor for thyroxine and tri-iodothyronine on integrin αvβ3. Recognition of divergence of action of the pro-oncogenic L-thyroxine (T4) from pro-metabolic 3,5,3'-triiodo-L-thyronine (T3) has enabled clinical implementation whereby exogenous T3 may replace exogenous (or endogenous) T4 to maintain clinical euthyroid hypothyroxinemia that results in significantly better survival in advanced cancer patients without the morbidity of clinical hypothyroidism.

Keywords: L-thyroxine; cancer; euthyroid hypothyroxinemia; hypothyroidism; integrin αvβ3; thyroid hormone receptor.

Figure 1

(A) Actions of thyroid hormone are genomic or non-genomic in mechanism. (B) Specific non-genomic actions.

Figure 2

Non-genomic actions of the hormone that begin at integrin αvβ3 include regulation of intracellular trafficking of specific proteins to the nucleus and serine phosphorylation of some of these proteins in the course of nuclear entry. Directed to the nucleus from the cytoplasm, some of these proteins might be involved in modulation of transcription of specific genes and in cell proliferation. These pathways depend on activation of phospholipase C (PLC), protein kinase C (PKC), mitogen activated protein kinase (MAPK)1, and MAPK2. T4 non-genomically rapidly activates actin polymerization in hypothyroid astocytes and osteoblastic cells (15). Reprinted with permission from Hercbergs et al. (16).

Figure 3

MRI of brain of a 42 year old female with recurrent glioblastoma showing significant mass reduction with free thyroxine depletion at 4 months. Left, pre-thyroxine depletion; right, 4 months later. The patient survived for 3 years. Reprinted with permission from Hercbergs et al. (4).

Figure 4

MRI images of a 67 year old female patient who was deteriorating neurologically with hemiplegia unresponsive to high dose dexamethasone. Discontinuation of L-T4 was followed within 1 week by significant clinical improvement and tumor regression. Arrows point to tumor mass, showing reduction in size in all dimensions following cessation of exogenous L-T4.

Figure 5

CT images of esophageal sarcoma metastatic with cardiac infiltration and cardiac failure, right image is on exogenous L-T4, left image is post L-T4 discontinuation and oral cyclophosphamide. Patient improved clinically and was discharged from intensive care.