Chemotherapy is a double-edged sword. It is anticancer because of its cytotoxicity. Paradoxically, by increasing chemoresistance and cancer metastasis, it is also procancer. However, the underlying mechanisms for chemotherapy-induced procancer activities are not well understood. Here we describe the ability of paclitaxel (PTX), a frontline chemotherapeutic agent, to exacerbate metastasis in mouse models of breast cancer. We demonstrate that, despite the apparent benefit of reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung. At the primary tumor, PTX increased the abundance of the tumor microenvironment of metastasis, a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream. At the metastatic lung, PTX improved the tissue microenvironment (the "soil") for cancer cells (the "seeds") to thrive; these changes include increased inflammatory monocytes and reduced cytotoxicity. Importantly, these changes in the primary tumor and the metastatic lung were all dependent on Atf3, a stress-inducible gene, in the noncancer host cells. Together, our data provide mechanistic insights into the procancer effect of chemotherapy, explaining its paradox in the context of the seed-and-soil theory. Analyses of public datasets suggest that our data may have relevance to human cancers. Thus, ATF3 in the host cells links a chemotherapeutic agenta stressor-to immune modulation and cancer metastasis. Dampening the effect of ATF3 may improve the efficacy of chemotherapy.chemotherapy | metastasis | stress response | immune modulation | ATF3 M odern chemotherapy can reduce tumors to an undetectable level; however, in many cases the tumors relapse, with recurrence in the original, regional, or distant sites (1-3). The mechanisms for relapse are multifaceted and complex, including intrinsic changes in cancer cells and changes in the noncancer cells in the host-the organism carrying the cancer (4-9). Although the traditional concept is that chemotherapeutic drugs provide selection pressure for drug-resistant cancer cells to thrive, recent studies showed that chemotherapeutic drugs actually induce procancer changes (reviewed in refs. 4-9 and in the references cited below). Thus, chemotherapy is a double-edged sword: It is anticancer because of its cytotoxicity on cancer cells but also can be procancer by inducing changes in cancer and/or host cells. For cancer cell-intrinsic changes, chemotherapeutic drugs have been shown to induce the migration/invasion of cancer cells (10) and to up-regulate the expression of some antiapoptotic genes (11). For noncancer cells, chemotherapy theoretically can affect all host cells, because it is administered systemically. Advances in this nascent field have benefited greatly from the extensive literature on cancerhost interaction in the recent decades (5-7, 12). Although endothelial cells have been shown to play a role in mediating the procancer effect of chemotherapy (13-15), various reports als...

The sodium iodide symporter (NIS) is a classical iodide pump typically localized within the cell plasma membrane in thyroid cells, where NIS expression is believed to ensure success of mainstay radioiodide therapy in thyroid cancers. Although radioiodide uptake is generally reduced in thyroid cancer tissue, intracellular nonmembranous NIS has been reported to increase, suggesting that NIS serves a pump-independent function. Thyroid cancer is one of the major component cancers of Cowden syndrome, a subset of which is caused by germline mutations in In this study, we explored the noncanonical tumorigenic role of NIS in thyroid cancer cells in relation to PTEN signaling. PTEN knockdown in thyroid cancer cell lines stabilized intracellular NIS protein by promoting an interaction with NIS-LARG (leukemia-associated RhoA guanine exchange factor). Increased protein levels of cytoplasmic NIS enhanced RhoA activation and resulted in a promigration tumorigenic phenotype. Inhibition of NIS glycosylation through activation of the PI3K/AKT/mTOR signaling pathway contributed to mislocalization of NIS in the cytoplasm, facilitating its nonpump tumorigenic function through an interaction with LARG, which predominantly localized in the cytoplasm. Moreover, PTEN or PI3K/AKT/mTOR signaling could affect DPAGT1, a glycosylating enzyme involved in the initial step of N-linked glycosylation, to inhibit glycosylation of NIS. In summary, our results elucidate a pump-independent, protumorigenic role for NIS in thyroid cancer via its cross-talk with PTEN signaling. A novel pump-independent protumorigenic role of nonmembranous NIS challenges the presumption that radioiodine treatment of thyroid cancer is ineffective when transmembrane NIS is not expressed. .

Active surveillance (AS) can be considered as an alternative to immediate surgery in low-risk papillary thyroid microcarcinoma (PTMC) without clinically apparent lymph nodes, gross extrathyroidal extension (ETE), and/or distant metastasis according to American Thyroid Association. However, in the past AS has been controversial, as evidence supporting AS in the management of PTMC was scarce. The most prominent of these controversies included, the limited accuracy and utility of ultrasound (US) in the detection of ETE, malignant lymph node involvement or the advent of novel lymph node malignancy during AS, and disease progression. We summarized publications and indicated: (1) US, performer-dependent, could not accurately diagnose gross ETE or malignant lymph node involvement in PTMC. However, the combination of computed tomography and US provided more accurate diagnostic performance, especially in terms of selection sensitivity. (2) Compared to immediate surgery patients, low-risk PTMC patients had a slightly higher rate of lymph node metastases (LNM), although the overall rate for both groups remained low. (3) Recent advances in the sensitivity and specificity of imaging and incorporation of diagnostic biomarkers have significantly improved confidence in the ability to differentiate indolent vs. aggressive PTMCs. Our paper reviewed current imagings and biomarkers with initial promise to help select AS candidates more safely and effectively. These challenges and prospects are important areas for future research to promote AS in PTMC.

Background: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. Methods: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAF V600E , NRAS Q61R , and HRAS Q61R in AA patients whose primary tumor samples were available (28/55). Results: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAF V600E appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAF V600E , NRAS Q61R , and HRAS Q61R. Conclusions: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insights into the mechanisms underlying RAI-R disease.