**7. Pancreatic carcinoma**

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

**5. Glioblastoma**

glioblastoma [27].

been tested [27].

**6. Renal cell carcinoma**

in glioblastoma xenografts [25].

implicating the thyroid hormone receptor on integrin αvβ3 in the response. These cell lines express ERα As is the case in human breast cancer cells that express ER, the estrogen receptor is subject to activation/phosphorylation in the presence of T4. ER activation is associated with cancer cell proliferation quantitated by PCNA expression and thymidine incorporation. The specific ERα antagonist compound, ICI 182,770, diminished the activation by T4 of the estrogen receptor, as well as the stimulation of proliferation by T4. The growth of non-small cell (H1299) lung carcinoma xenografts is reversed by unmodified and chemically modified tetrac [23], consistent with a critical role for αvβ3 in the regulation of tumor growth.

More information available about T4 action on lung cancer is limited. Euthyroid hypothyroxinemia appears to slow the course of metastatic lung carcinoma [27].

In preclinical studies, T4 has been shown to be a growth factor for gliomas [21], and the actions of chemically modified tetrac molecules at the thyroid hormone receptor on integrin αvβ3 significantly increased transcription of a panel of proapoptotic genes (*p53*, *p21*, *PIG*, *BAD*) [7]. The latter results imply that T4 action at the integrin may undesirably either decease or not affect expression of these genes. In a limited *in vitro* study, T3 restricted glioblastoma cell proliferation [42] and preclinical studies have also shown that NDAT—which limits access of T4 to its receptor on integrin αvβ3 on tumor cells—suppresses growth and is anti-angiogenic

In 2003, chemical induction of mild hypothyroidism with propylthiouracil (PTU) was shown in patients with recurrent, high-grade glioblastoma to be associated with significant prolongation of survival [43]. More recently, euthyroid hypothyroxinemia has significantly extended survival in patients with end-stage

Induction of euthyroid hypothyroxinemia has been effective in prolonging survival of the few glioblastoma patients with end-stage disease in whom it has

Among the side effects of chemotherapeutic tyrosine kinase inhibitors (TKIs) used in management of renal cell carcinoma (RCC) is induction of preclinical primary hypothyroidism. The "preclinical" state is an elevation of circulating TSH with normal range serum T4 and T3 concentrations. An extensive clinical literature documents that response of metastatic RCC to TKIs sorafenib and sunitinib is importantly enhanced when drug-induced hypothyroidism complicates tumor management [28, 30, 44–48]. TKIs may cause hypothyroidism in up to 40% of treated patients. The therapeutic response to the recognition of druginduced preclinical primary hypothyroidism in RCC patients was administration of exogenous T4 to the point of returning host TSH to the normal range. In the noncancerous patient with preclinical hypothyroidism, the American Thyroid Association has endorsed a strategy of replacement thyroid hormone as needed to prevent symptoms of hypothyroidism and maintain serum TSH below 10 mIU/ mL [49]. This approach may be adequate to take advantage of the TKI support that preclinical hypothyroidism provides with reduction in circulating T4 within the

**4**

normal range.

Pancreatic cancer is an aggressive tumor locally and metastasizes regionally and systemically with sufficient frequency to have a very unsatisfactory 5-year survival. The relevance of thyroid hormone to tumor behavior has been shown in xenograft studies [50]. Unmodified and chemically modified tetrac in 15-day studies reduced xenograft size by up to 50% and reduced graft vascularity. Tumor gene expression studies showed that chemically modified tetrac acted via αvβ3 to reduce epidermal growth factor receptor (EGFR) gene and anti-apoptotic XIAP gene transcription and to increase expression of pro-apoptotic p53 and anti-angiogenic thrombospondin 1. The implication of these results is that T4—whose binding to αvβ3 is inhibited by tetrac—may play an important tumor support role in this form of cancer.

In contrast to RCC, there is not a significant literature on chemotherapeutic drug-induced hypothyroidism in patients with pancreatic carcinoma. Induction of euthyroid hypothyroxinemia appears to slow the course of advanced pancreatic cancer [27].

## **8. Discussion**

At the cancer cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3, T4 is an active hormone, supporting a variety of critical tumor cell functions [5, 10, 26]. In contrast, T4 within normal cells and cancer cells can serve as a prohormone source for T3. T4 is the standard of care for management of hypothyroidism [49].

A small minority of hypothyroid patients coincidentally have an experience with cancer of various types, as pointed out above. The behavior of the tumors is reported in most clinical studies of this combination of diseases to be less aggressive. But interpretation of the data is sometimes difficult because a distinction may not be made between T4-treated and untreated spontaneous hypothyroid states and the appearance or behavior of the cancer. However, substantial information is now available about the link of hypothyroid state to tumor behavior in those patients in whom hypothyroidism is a side effect of chemotherapy, e.g., TKI use in RCC patients [28, 47, 51], or the clinical use of euthyroid hypothyroxinemia in patients with advanced cancers [27].

A body of preclinical evidence also exists to indicate that T4 stimulates proliferation of a variety of tumors, and this effect is initiated at a plasma membrane receptor for thyroid hormone that is generously expressed in cancer cells [5]. At this receptor site, T4 is also anti-apoptotic [5] and supports tumor-relevant angiogenesis [5]. The integrin may also be involved in tumor cell radioresistance [32, 33].

Against this background, we raise the issue of whether prescription of T4 replacement in hypothyroid patients with concurrent cancer should be routine. T3 is not active at physiological concentrations at the integrin receptor for thyroid hormone

and we have shown that T3 can be substituted for endogenous T4 in euthyroid patients with cancer with a result of improved survival and, in some cases, reduction in tumor size. Thus, we feel that the use of T3 replacement can be endorsed in patients with spontaneous or TKI-induced hypothyroidism and cancer. A disadvantage is that T3 must be administered more than once daily because of its short half-life.

A particularly interesting example of the complexity of the relationships of thyroid hormone and cancer is the capacity of T4 to activate ERα in ER-positive breast cancer cells in the absence of estrogen [15]. In addition, T4 is able to promote trafficking of ER from cytoplasm to nucleus [52]. Thus, ER in breast cancer of the postmenopausal euthyroid woman remains a functional component of the tumor.

The setting of thyroid cancer and concomitant hypothyroidism management is not included in the sections above in this review but has been discussed elsewhere by the current authors [53]. Hypothyroidism in the setting of thyroid cancer may of course be a consequence of radiation therapy of the tumor. Exogenous T4 may be administered in patients with thyroid cancers to suppress endogenous thyrotropin (TSH) that may support thyroid tumor cell proliferation. What we have recommended in the context of thyroid cancer and hypothyroidism or T4-suppression of endogenous TSH with T4 and intractable tumor behavior is that the use of T3 be considered [53] as, respectively, hormone replacement or vehicle to suppress host TSH.
