Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma

Background

A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC.

Methodology/Principal Findings

Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a “microglia-like” appearance on these cells which we termed “Ramified TAMs” (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells.

Conclusion

ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined.     

Immunoreactive-beta-endorphin, -adrenocorticotropin and -calcitonin in extracts of anaplastic or differentiated (rat) medullary thyroid carcinoma.

Fifteen analogs of luliberin (2, LRH) were synthesized by the solid phase method and examined for their ability to block ovulation in the rat. Two analogs, [Ac-DAla¹,DPhe²,DTrp^3,6]-LRH and [Ac-DPhe¹,DPhe²,DTrp^3,6]-LRH, each blocked ovulation at a single injection dose of 250 μg administered at noon on the day of proestrus; three peptides, [Ac-DPro¹,DPhe²,DTrp^3,6]-LRH, [Ac-DThi¹,DPhe²,DTrp^3,6]-LRH and [Ac-DTrp¹,DPhe²,DTrp^3,6]-LRH, were effective at doses of 500 μg each; and four others, [Ac-DTrp¹,DPhe²,DTrp³,DTrp(Nps)⁶]-LRH, [Chlorambucil-DPhe¹, DPhe², DTrp^3,6]-LRH, [1,DThi²,DTrp^3,6]-LRH and [(2-DLys⁶]-LRH, gave partial inhibition at doses tested.     

Metastatic anaplastic carcinoma of the thyroid mimicking squamous cell carcinoma: report of a case of a challenging cytologic diagnosis

BACKGROUND: The probability of anaplastic transformation in a differentiated thyroid carcinoma (DTC) is <2%. Admixture of DTC and undifferentiated carcinoma can occasionally be found in thyroidectomy specimens, or the undifferentiated tumor may develop in metastatic foci months or years after removal of the primary tumor. CASE: Anaplastic transformation of a metastatic DTC was diagnosed at autopsy in a 71-year-old female. At the time of her total thyroidectomy for follicular carcinoma, she already had several lung nodules, which diminished in size upon 131I treatment. Five years later the patient developed a new, pleura-based lung mass. The mass extended along the paraspinal soft tissue and involved the kidney. Fine needle aspiration biopsy of the paraspinal mass resulted in a diagnosis of metastatic squamous cell carcinoma. Two months later the patient died. Histologic evaluation of the lung nodules and pleura-based mass revealed areas of follicular carcinoma intermixed with a various patterns of undifferentiated carcinoma. The paraspinal and kidney mass consisted entirely of anaplastic tumor, including areas of squamoid differentiation. CONCLUSION: In patients with a history of DTC who develop a rapidly growing mass elsewhere, a possibility of metastatic DTC with anaplastic transformation must be considered.     

Heterotransplantability of human anaplastic thyroid carcinoma line (HOTHC) in nude mice, and biological properties of the heterograft

The heterotransplantability of HOTHC line (human anaplastic thyroid carcinoma) into the subcutis of BALB/c nude mice and the biological properties of grafts were discussed. (1) The HOTHC line showed high transplantability, and 1 x 10(4) cells produced anaplastic carcinoma (giant cell type) containing the colloid-like substance. (2) The grafted tumors grew rapidly and the mice were dead within 2 months after transplantation. (3) The number of leukocytes (neutrophils) of mouse peripheral blood increased as the tumor size increased, and the leukocyte count returned to a normal value after removal of the tumor. (4) The conditioned media of HOTHC line formed colonies of granulocytes (neutrophils) on soft agar. These phenomena revealed that HOTHC is a granulocyte-colony stimulating factor-producing line. (5) The conditioned media of HOTHC line showed promoting-effect on neovascularization on the chorioallantoic membrane.     

Osteoclastomalike anaplastic carcinoma of the thyroid. Diagnosis by fine needle aspiration cytology

Fine needle aspiration (FNA) of a neck mass yielded cytologic specimens containing two cell populations: multinucleated giant cells and smaller, round-to-oval, undifferentiated malignant cells. The giant cells were frequently so numerous as to obscure the other cells. The FNA cytodiagnosis of a rare anaplastic thyroid carcinoma containing osteoclastic giant cells was substantiated by the subsequent exploratory surgery and biopsy specimen. Immunohistochemical staining suggested a dual origin of the two cell populations.     

Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study

Molecular Biology Reports - Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that...     

BMP-7-induced cell cycle arrest of anaplastic thyroid carcinoma cells via p21(CIP1) and p27(KIP1).

The aim of the present study was to investigate the effect of bone morphogenetic protein (BMP-7) on thyroid carcinoma cell growth. Addition of BMP-7 inhibited the proliferation of four out of six human anaplastic thyroid carcinoma cell lines, observed as decreased incorporation of (3)H-thymidine and decreased cell number. The growth inhibitory effect was cell density-dependent; sparse cells were inhibited by BMP-7 whereas dense cells were not. Cell cycle analysis by flow cytometry showed an increased fraction of cells in the G1-phase and subsequent decrease in both S- and G2/M-phase after BMP-7 stimulation. Furthermore, BMP-7 caused an upregulation of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27, decreased activity of Cdk2 and Cdk6, and hypophosphorylation of the retinoblastoma protein (pRb). These findings suggest a growth inhibitory effect of BMP-7 on anaplastic thyroid carcinoma cells by inhibition of Cdk activity shifting the Rb protein to the hypophosphorylated state.     

Role of chemotherapy in the treatment of anaplastic thyroid cancer --personal observations]

Results of chemotherapy applied in 23 patients with anaplastic thyroid cancer are presented. Chemotherapy combined with local treatment is a suggested therapy for treatment the locally advanced anaplastic thyroid cancer.     

Augmentation of lenvatinib efficacy by topical treatment of miR-634 ointment in anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is one of the most lethal types of human tumors. Lenvatinib can improve the disease control and prognosis in patients with ATC. However, there is an unmet need to develop a therapeutically safer and non-invasive strategy that improves the efficacy of lenvatinib for advanced ATC tumors, which grow larger close to the skin. We previously demonstrated that the topical application of an ointment incorporating tumor suppressive microRNA (TS-miR), miR-634, is a useful strategy as a TS-miR therapeutics. Here, we found that the overexpression of miR-634 synergistically increased lenvatinib-induced cytotoxicity by concurrently downregulating multiple genes related to cytoprotective processes, including ASCT2, a glutamine transporter, in ATC cell lines. Furthermore, the topical application of a miR-634 ointment on subcutaneous tumors effectively augmented the anti-tumor effects of lenvatinib in an ATC xenograft mouse model. Thus, we propose topical treatment of a miR-634 ointment as a rational strategy for improving lenvatinib-based therapy for ATC.     

Use of oral chemotherapeutic agent,chlorambucil, as palliative treatment of thryoid adenocarcinoma in a golden-headed lion tamarin (Leontopithecus chrysomelas)

This case report describes the use of chlorambucil in a 7.5-year-old golden-headed lion tamarin (Leontopithecus chrysomelas) as palliative therapy for thyroid adenocarcinoma. Treatment was initiated at 0.1 mg/kg orally once daily. No physical abnormalities or substantial changes in complete blood cell counts and thyroid hormone levels from serial samples were detected.