SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID

 SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID (Failed Beheard application 😉)

Research background and summary 

What rare disease do you study?

 A: SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA OF THYROID

The general disease area of the rare disease you study. e.g. Immune/inflammatory disorder, metabolic disorder, neurodegenerative disorder, etc... 

A: CANCER BIOLOGY/ INFLAMMATION

Specific Aims (Less than 1000 words) This section should include background, hypothesis, specific aims, and significance. 

A:

BACKGROUND

Sclerosing mucoepidermoid carcinoma with eosinophils of thyroid (SCEME) is a rare thyroid carcinoma. Although it is believed to take a slow, indolent approach to grow, the carcinoma can cause complications due to involvement of large part of the thyroid and neck. Apart from the involvement of thyroid gland, SCEME is also known to metastasize to different body parts, further complicating the prognostic outcome. The interesting part of the clinical picture is sclerosis and fibrosis of the involved part of the thyroid gland, and Hashimoto’s Thyroiditis (HT) in non-involved portion of the thyroid. The stroma shows infiltration of eosinophils, lymphocytes and plasma cells. 

SCEME has been found to be associated mostly with papillary thyroid cancer (PTC), and few cases with follicular or anaplastic thyroid cancer. There are two opposing views regarding the origin of SCEME, first one being a follicular cell origin. Other authors have suggested a primary involvement of salivary gland and secondary involvement of thyroid and neck. There are no research conducted so far on SCEME and no mouse models also exist. However, the granulomatous autoimmune thyroiditis (SAT) mouse model comes close to mimicking SCEME. 

SAT model was first described by Dr. Helen Braley-Mullen’s lab using NOD.H2h4 strain of mice. The NOD.H2h4 mice on K-haplotype spontaneously develop autoimmune thyroiditis (mimicking Hashimoto’s thyroiditis), when given sodium iodide in drinking water. This mouse strain has been described to be suitable for the study of two autoimmune diseases- Hashimoto’s thyroiditis and Sjogren’s syndrome, two components which form part of SCEME. The infiltrate in the thyroids is typically that of mononuclear cells where CD4 T cells are predominant. Their lab also described another version of SAT model with knockdown of interferon-gamma from the thyroid. Interestingly this version of SAT has extensive infiltration of eosinophils, along with CD4 T cells. This model however does not lead to thyroid cancer, but rather thyroid cell hyperplasia. 

The role of HT in contributing towards development of thyroid cancer has always been controversial. However, many clinical studies suggest better prognosis, when HT is found associated with thyroid cancer. Work done in SAT mouse model has demonstrated the secretion of various pro-inflammatory cytokines by infiltrating CD4 T cells. These cytokines however can contribute to the cancer cell death due to the TNF-alpha cell death pathway along with ROS cell death pathway, which might explain better thyroid cancer prognosis. Therefore loss of these cytokines coupled with HT might shift the infiltrate from lymphocytic heavy to high in eosinophils. This shift in the infiltrate might be responsible for hyperplasia and fibrosis. This event coupled with the active transformation pathways such as those of PTC might lead to SMECE.

HYPOTHESIS

We therefore hypothesize that local loss of inflammatory cytokine expression (TNF-alpha or IFN-gamma etc) in thyroid coupled with loss of tumor suppressors (such as cell death pathway regulators) and activation of transformation pathways leads to the development of SCEME.

SPECIFIC AIMS

To address the hypothesis, we are going to do as follows:

  1. We will first develop NOD.H2h4 KO mice with thyroid-specific KO of pro-inflammatory cytokines such as IFN-gamma, TNF-alpha, interleukin-1 (IL-1) etc. The phenotype of these mice will be studied with respect to SAT, infiltrating cells, fibrosis, hyperplasia.

  2. Few tumor suppressors such as pRb and p53 proteins will be knocked down from thyroid (NOD.H2h4) and these mice will be bred with cytokine KO mice on NOD.H2h4 background. The phenotype of these dual KO mice will be examined with respect to SAT, infiltrating cells, fibrosis and tumor development.


DISCUSSION 

We expect the pro-inflammatory cytokine KO mice to have fibrosis, hyperplasia, and eosinophilic rich infiltrate, but no tumor formation. However, when combined with p53 or pRb KO mice, the resulting phenotype should resemble that of SCEME. In the event of non-formation of tumors, we will further combine them with thyroid –specific expression of various PTC causing oncogenes such as BRAF-V600E. 

SIGNIFICANCE

SCEME is a rare thyroid neoplasm with a unique phenotype. Although described as indolent tumor, few cases have been associated with metastatic spread. This particular metastatically spreading SCEME has been termed as aggressive. However, till date no explanations have been forthcoming regarding the origin of the tumor, which is important to develop targeted therapeutic strategies. So far the treatment strategies involve surgical intervention which is beneficial in the absence of metastatic spread or recurrence of the neoplasm. Since a part of SCEME resembles the SAT-mouse model, this application was an attempt to further explore the biology of SCEME. So far the influence of pro-inflammatory cytokines on the development and progression of thyroid cancers have not been explored properly. One PTC type associated with the pro-inflammatory cytokines is RET/PTC3 oncogene mediated PTC. RET/PTC3 oncogene is known to express various pro-inflammatory cytokines but this does not make this tumor aggressive. Our unpublished work suggests that these cytokines are also responsible for ROS and TNF-alpha mediated cell death of the cancer cells. Speculating further we also feel that infiltrating T cells from HT would weaken the thyroid cancer progression. pRb and p53 are tumor suppressors ubiquitously involved in cancers and in epidermoid carcinomas as well. Combining all these together would be able to help us understand SCEME’s origins.

Approach


  1. Repository live mouse strains from Jackson labs to procure NOD.H2h4 mice and NOD.H2h4 IFN-gamma KO mice, if available.

As explained in the specific aims, our whole approach involves using NOD.H2h4 mice which are readily available in Jackson’s lab repository. For our work, we would ideally need one or two breeding pairs. Dr. Braley Mullen was in negotiations with Jackson labs on depositing NOD.H2h4-IFN-gamma KO mice (personal communication). If available, we would procure one or two breeding pairs from Jackson labs. The colony produced from these mice will be used further. IFN-gamma and TNF-KO mice on NOD background are also available from Jackson labs. These mice will be bred with NOD.H2h4 mice to develop NOD.H24-cytokine KO mice.

  1. Custom mouse model (Taconic)).

To develop pRB and Trp53 NOD mice, we will use conventional techniques to knockdown gene from the animal or from the thyroid. In the event of technical difficulties, conventional gene knockdown will be carried out, knocking down genes in all organs and tissues.


https://www.linkedin.com/in/suresh-kari-9357783/

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