Abstract
Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer cell motility and invasion, and immune system escape. Our team has previously demonstrated a higher serum level of Gal-1 in patients with differentiated thyroid cancers versus healthy patients, and explored, by a knockdown strategy, the effect of Gal-1 silencing on cell proliferation and invasion in vitro, and on tumor and metastasis development in vivo. OTX008 is a calixarene derivative designed to bind the Gal-1 amphipathic β-sheet conformation and has previously demonstrated anti-proliferative and anti-invasive properties in several cancer cell lines including colon, breast, head and neck, and prostate cancer lines. In the current work, the impacts of OTX008 were evaluated in six thyroid cancer cell lines, and significant inhibitions of proliferation, migration, and invasion were observed in all lines expressing high Gal-1 levels. In addition, the signaling pathways affected by this drug were examined using RPPA (reverse phase protein array) and phosphoprotein expression assays, and opposite regulation of eNos, PYK2, and HSP27 by OTX008 was detected by comparing the two anaplastic lines 8505c and CAL 62. Finally, the sensitive 8505c line was xenografted in nude mice, and 3 weeks of OTX008 treatment (5 mg/kg/day) demonstrated a significant reduction in tumor and lung metastasize sizes without side effects. Overall, OXT008 showed significant anti-cancer effects both in vitro and in vivo in thyroid cancer lines expressing Gal-1, supporting further investigation of the molecular mechanisms of the drug and future clinical trials in patients with anaplastic thyroid cancer.
Highlights
We demonstrated the implication of Gal-1 in thyroid cancer by using a knockdown model showing the inhibition of TPC-1 cell migration, 8505c cell proliferation, and invasion in vitro, in addition to a significant decrease in tumor and metastasis development in vivo [9]
The concentration–response curves showed similar profiles for all lines, except for the CAL62 line, which appeared to be significantly more resistant to the inhibitor. These curves allow assessment of the IC50 values defined as the OTX008 concentrations able to inhibit cell proliferation by 50%
Our study demonstrated the therapeutic potential of OTX008 in thyroid cancer cells based on the inhibition of proliferation and invasion in vitro, in addition to reduction in tumor mass and the development of lung metastasis in a xenograft anaplastic mouse model
Summary
Thyroid cancer is the most common endocrine cancer and accounts for around 2% of total cancers diagnosed globally, corresponding to 567,233 new cases in 2018 and ranking in 9th place for incidence. The incidence of thyroid cancer has increased in many countries since the early 1980s, probably due to the increase in the diagnosis of papillary thyroid cancer in relation to the improvements in diagnostic methods [1]. Despite the fact that the overall survival rates of the main forms of thyroid cancer (papillary and follicular forms) are generally good, some forms, such as anaplastic carcinomas and radioactive iodine (RAI). Study of the tumor microenvironment interactions, and understanding of drug resistance mechanisms, are crucial in the cancer field, for thyroid anaplastic cancers, for which no therapy currently seems to improve the prognosis at one year
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