Reflections

  Significance Overview   RET/PTCs are a group of oncogenic fusion proteins derived from the proto-oncogene c-RET, structurally related to a family of receptor tyrosine kinases (1-3). RET/PTCs result from joining the carboxy-terminus of fusion partners with the amino-terminus of c-RET, leading to constitutively active kinase. Of the 11 different fusion genes reported, RET/PTC1 or RP1 and RET/PTC3 or RP3 are the most prevalent (1). In the case of RP3, the amino terminus is derived from the androgen receptor-associated protein, ARA-70 (Fig. 1) (4). RP3 drives three different pathways that strongly influence biological properties of the tumor. First, the constitutively active c-terminal RET kinase domain activates RAS/BRAF/MEK/ERK, PI3K/AKT, p38MAPK, and JNK pathways leading to thyrocyte transformation (5). Second, kinase activity leads to precocious phosphorylation of RP3 itself and other intracellular proteins that provide tumor-specific targets for the adaptive immu...

  RET/PTC3 Oncogene's Inflammatory Properties and Hashimoto's Thyroiditis   Various components of the ability to fight of infection in a host are collectively termed as immune system. Swelling, redness, pain and heat at the site of infection are hallmark of the active immune system and are defined as inflammation. Generally, more robust the inflammatory reaction is, the better it is for the host to clear the infection. Cancers are different as they are said to be actively causing the development of inflammation. The reason is that increased blood flow to the site of cancer brings more and more nutrients and other mediators which contradictorily help expand the cancer growth. We however believe that to be inaccurate, at best reflecting certain cancers only. We investigate papillary thyroid carcinoma (PTC) which is one of the most prevalent endocrine tumor known, accounting for about 85% of the thyroid malignancies. The incidence of thyroid cancers is on the rise too, in USA and...

  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 interest...

Warburg's effect is quoted many times to describe the faulty metabolic pathways in tumor cells. Tumor cells which are rapidly dividing are known to create a hypoxic microenvironment which does not support glucose oxidation. Under these circumstances, glycolysis becomes a dominant metabolic pathway to generate energy for the rapidly dividing tumor cells. However, this may not be the complete story. In recent years, there has been a tremendous amount of work being done to explore the metabolic pathways involved in various tumors. All this now depicts a newer reality where glycolysis instead of being "The pathway" is now thought to be one of the pathways used by the tumor cells. Of interest are the protein metabolic pathways such as glutamine and proline pathways, The nucleic acid metabolic pathways and my present interest, the fatty acids pathways.  If we consider that alternative pathways such as fatty acid oxidation, protein metabolic pathways,  then all the proteins ...

If you read about thyroid cancer, everyone agrees that its incidence is on the rise. In recent months, there has been lots of press coverage as how this increased thyroid incidence is due to overdiagnosis. To illustrate the overdiagnosis with an example, we need to take a look at South Korea. There was a huge increase in the incidence of thyroid cancer in South Korea which was blamed on overdiagnosis . But a recent review article on this topic cautions; not so fast . Thyroid cancers form about 2.1% of total cancer diagnoses worldwide, with women disproportionately affected, accounting for about 77% of the cases. The phenomenon of more women patients than men is unique to thyroid pathology and is also seen in Hashimoto's thyroiditis and Graves' disease. Majority of thyroid cancers are termed differentiated with two main subtypes, papillary thyroid cancers (PTC) and follicular thyroid cancers (FTC). The increased incidence of the thyroid cancer is mainly attributed to increas...

Follicular Thyroid cancer and new driver mutations New developments on thyroid cancer front this week. A research group from South Korea  published an article on the transcriptional and mutational landscape of follicular (FTC) and papillary thyroid cancers (PTC). The reason this is big news is that this is the first time when a comprehensive data is being published on FTCs. Comprehensive data on PTC already exist as it was published in 2014 . I am not going to discuss the whole of the article but there was few interesting points which caught the eye. One of which was that the authors proposed new driver mutations for thyroid cancer, of the many two of them are EZH1 (a member of polycomb group protein complex) and LKB1. The interesting part came from another group in Italy who published a paper in JCI  about role of EZH1 in development of thyroid adenomas. The paper describes the role of cAMP signaling from TSHR mutations which when combined with EHZ1 mutations lead t...

LKB1 conundrum: LKB1 in thyroid cancer LKB1 is a known tumor suppressor. first identified in  Peutz Jeghers Syndrome , characterized by general hamartomatous polyposis leading to the formation of multiple tumors at several sites in the body. Loss or inactivation of LKB1 has been shown in  lung cancer  and  other   organ systems  confirming its role as a tumor suppressor. LKB1 is known to act as a tumor suppressor through various different mechanisms. One of the important mechanisms being activation of downstream tumor suppressor, AMPK. AMPK in turn inhibits mTOR which is important for regulation of metabolic pathways in tumor cells. However,  recent evidence  suggests that AMPK might not be a tumor suppressor but  promote tumor growth  under certain contexts. There are reports suggesting both AMPK and mTOR to be active in tumors without compromising the action of one another. This is turn also applies to the protein upstream of AMPK, ...

LKB1 conundrum: LKB1 in thyroid cancer LKB1 is a known tumor suppressor. first identified in Peutz Jeghers Syndrome, characterized by general hamartomatous polyposis leading to the formation of multiple tumors at several sites in the body. Loss or inactivation of LKB1 has been shown in lung cancer and other organ systems confirming its role as a tumor suppressor. LKB1 is known to act as a tumor suppressor through various different mechanisms. One of the important mechanisms being activation of downstream tumor suppressor, AMPK. AMPK in turn inhibits mTOR which is important for regulation of metabolic pathways in tumor cells. However, recent evidence suggests that AMPK might not be a tumor suppressor but promote tumor growth under certain contexts. There are reports suggesting both AMPK and mTOR to be active in tumors without compromising the action of one another. This is turn also applies to the protein upstream of AMPK, i.e. LKB1. Therefore both LKB1-AMPK have now been termed as cont...