Exosomes are extracellular vesicles secreted by most eukaryotic cells and participate in intercellular communication. The components of exosomes, including proteins, DNA, mRNA, microRNA, long noncoding RNA, circular RNA, etc., which play a crucial role in regulating tumor growth, metastasis, and angiogenesis in the process of cancer development, and can be used as a prognostic marker and/or grading basis for tumor patients. Hereby, we mainly summarized as followed: the role of exosome contents in cancer, focusing on proteins and noncoding RNA; the interaction between exosomes and tumor microenvironment; the mechanisms that epithelial-mesenchymal transition, invasion and migration of tumor affected by exosomes; and tumor suppression strategies based on exosomes. Finally, the application potential of exosomes in clinical tumor diagnosis and therapy is prospected, which providing theoretical supports for using exosomes to serve precise tumor treatment in the clinic.

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Exosomes: key players in cancer and potential therapeutic strategy.

Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies. We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation. Special emphasis was given to the role of EVs in the transfer of drug resistant traits and to the EV cargo responsible for this transfer, both between cancer cells or between the microenvironment and tumor cells. Finally, we reviewed evidence for the increased release of EVs by drug resistant cells. A timely and comprehensive understanding of how tumor EVs facilitate tumor initiation, progression, metastasis and drug resistance is instrumental for the development of innovative EV-based therapeutic approaches for cancer.

The Role of Extracellular Vesicles in the Hallmarks of Cancer and Drug Resistance.

The incidence of differentiated thyroid cancer has been increasing in the last decades all over the world. Such a steady growth cannot be entirely attributable to more intensive thyroid nodule screening and more sensitive diagnostic procedures. Several environmental factors have changed with sufficient rapidity in the same time frame and may represent credible candidates for this increase. They include modified iodine intake, lifestyle-associated risk factors, exposure to various toxic compounds, pollutants and xenobiotics, nutritional deficiencies, eating habits and comorbidities. Foremost, nutritional patterns have gained high interest as possible promoters and modifiable risk factors for thyroid cancer in recent years. The aim of this narrative review is to focus on the relationship between thyroid cancer and nutritional factors, dietary habits and obesity. Low iodine intake has been associated to increased risk of thyroid cancer, favoring the development of more aggressive histotypes. Moreover, correction of iodine deficiency can shift thyroid cancer subtypes toward less aggressive forms, without affecting the overall risk for cancer. Actually, evidence regarding the association between selenium and vitamin D deficiency and thyroid cancer is very limited, despite their well-known anti-cancer potentials, and the clinical usefulness of their supplementation is still uncertain in this setting. Albeit the relationship between single foods and thyroid cancer is difficult to examine, fish and iodine-rich foods, vegetables, and fruits might exert protective effects on thyroid cancer risk. Conversely, no clear association has been found for other foods to date. Lastly, a clear association between obesity and the risk of thyroid cancer, with more aggressive behavior, seems to emerge from most studies, likely involving variations in thyroid function and chronic inflammation mediated by cytokines, insulin, leptin and adiponectins. Although no definite association between dietary factors and thyroid cancer has been firmly established so far, some nutritional patterns, together with excessive weight, seem to play a relevant role in thyroid cancer carcinogenesis as well as in its severity and aggressiveness. These effects may play an additive role to the well-established one exerted by environmental carcinogens, such as pollutants and radiation exposure.

Nutritional status and follicular-derived thyroid cancer: An update

Background: In many risk-stratification systems, the decision to biopsy thyroid nodules is determined by their sonographic features and size. Nevertheless, even low-suspicion nodules are often biop...

Effect of Tumor Size on Risk of Metastatic Disease and Survival for Thyroid Cancer: Implications for Biopsy Guidelines.

Hepatocellular carcinoma (HCC) cells-secreted exosomes (exo) could stimulate M2 macrophage polarization and promote HCC progression, but the related mechanism of long non-coding RNA distal-less homeobox 6 antisense 1 (DLX6-AS1) with HCC-exo-mediated M2 macrophage polarization is largely ambiguous. Thereafter, this research was started to unearth the role of DLX6-AS1 in HCC-exo in HCC through M2 macrophage polarization and microRNA (miR)-15a-5p/C-X-C motif chemokine ligand 17 (CXCL17) axis. DLX6-AS1, miR-15a-5p and CXCL17 expression in HCC tissues and cells were tested. Exosomes were isolated from HCC cells with overexpressed DLX6-AS1 and co-cultured with M2 macrophages. MiR-15a-5p/CXCL17 down-regulation assays were performed in macrophages. The treated M2 macrophages were co-cultured with HCC cells, after which cell migration, invasion and epithelial mesenchymal transition were examined. The targeting relationships between DLX6-AS1 and miR-15a-5p, and between miR-15a-5p and CXCL17 were explored. In vivo experiment was conducted to detect the effect of exosomal DLX6-AS1-induced M2 macrophage polarization on HCC metastasis. Promoted DLX6-AS1 and CXCL17 and reduced miR-15a-5p exhibited in HCC. HCC-exo induced M2 macrophage polarization to accelerate migration, invasion and epithelial mesenchymal transition in HCC, which was further enhanced by up-regulated DLX6-AS1 but impaired by silenced DLX6-AS1. Inhibition of miR-15a-5p promoted M2 macrophage polarization to stimulate the invasion and metastasis of HCC while that of CXCL17 had the opposite effects. DLX6-AS1 mediated miR-15a-5p to target CXCL17. DLX6-AS1 from HCC-exo promoted metastasis in the lung by inducing M2 macrophage polarization in vivo. DLX6-AS1 from HCC-exo regulates CXCL17 by competitively binding to miR-15a-5p to induce M2 macrophage polarization, thus promoting HCC migration, invasion and EMT.

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Exosomal DLX6-AS1 from hepatocellular carcinoma cells induces M2 macrophage polarization to promote migration and invasion in hepatocellular carcinoma through microRNA-15a-5p/CXCL17 axis.

Central lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) is common. But the association between primary tumor characteristics and specific features of metastatic lymph nodes in PTC has not been fully identified. Determining risk factors for LNM may help surgeons determine rational extent of lymph node dissection. Data from 432 patients who underwent thyroidectomy with cervical lymph node dissection for PTC were retrospectively analyzed. The relationships between LNM to central compartment or lateral compartment and clinicopathologic factors were analyzed. Cox regression model was used to determine the risk factors for recurrence-free survival (RFS). Central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) were found in 216 (50.0%) and 65 (15.0%) patients, respectively. In the multivariate analysis for CLNM, patients < 45 years of age (OR 2.037, 95% CI 1.388–2.988, P < 0.001), extrathyroidal invasion (OR: 2.144, 95% CI 0.824–5.457, P = 0.011), vascular invasion (OR 13.817, 95% CI 1.694–112.693, P = 0.014), LLNM (OR 2.851, 95% CI 1.196–6.797, P = 0.014) and TNM Stage III–IV (OR 465.307, 95% CI 113.903–1900.826, P < 0.001) were independent predictors for high prevalence of CLNM. In the multivariate analysis for LLNM, tumor size more than 1cm (OR 3.474, 95% CI 1.728–6.985, P < 0.001) and CLNM (OR 5.532, 95% CI 2.679–11.425, P < 0.001) were independent predictors for high prevalence of LLNM. Moreover, tumor with T3–T4 stage, extrathyroidal invasion and CLNM were the significant factors related to the RFS. For patients with pre-operative risk factors of LNM, an accurate preoperative evaluation of central compartment or lateral compartment is needed to find suspicious lymph nodes. And prophylactic lymph node dissection should be performed in patients with high risk of CLNM. Moreover, we suggest performing close follow-up for patients with high risk of RFS.

Predictive factors for central lymph node and lateral cervical lymph node metastases in papillary thyroid carcinoma

Background Although multifocality is often observed in papillary thyroid carcinoma (PTC), the associations with clinicopathologic factors and the prognostic value are still controversial. We aimed to identify the risk factors for multifocality and bilaterality, and investigate the significance of multifocality on prognosis in all PTC, papillary thyroid microcarcinoma (PTMC) and non-PTMC. Methods: Data from 635 patients who underwent lobectomy/total thyroidectomy plus cervical lymph node dissection for PTC were retrospectively analyzed. Clinicopathological factors associated with multifocal PTC and bilateral PTC were investigated by univariate analysis. Multivariate Cox regression analyses was used to identify the clinicopathological prognostic factors for recurrence-free survival. Results: Multifocal and bilateral PTC were observed in 157 (24.7%) and 99 (15.6%) patients, respectively. The frequency of large diameter (>1.0 cm), extrathyroidal extension (ETE), vascular invasion and central lymph node metastases (CLNM) was higher in multifocal PTC than that of solitary PTC. Moreover, ETE, vascular invasion, CLNM and lateral lymph node metastasis (LLNM) were more frequent in patients with 3 or more tumor foci compared to those with 2 tumor foci and 1 tumor lesion. Bilateral PTC had higher rates of ETE and CLNM. Multifocality was found to be the predictor of recurrence in all PTC, PTMC, and non-PTMC. In addition, the risk of recurrence increased with increasing number of tumor foci in all multifocal PTC patients and multifocal non-PTMC patients. Conclusion: Although multifocality and bilaterality had more aggressive features in PTC, only multifocality was associated with the increased risk of recurrence. An increase in the number of tumors was associated with an increased risk of ETE, vascular invasion, CLNM and LLNM. The prognostic value of multifocality is particularly significant in non-PTMC patients.

Significance of multifocality in papillary thyroid carcinoma.

Background Exosomes are nano-sized biological vesicles released by many kinds of cells, which play an important role in tumor metastasis through transporting cytokines, RNAs and proteins. However, the molecular mechanisms of exosomes in hepatocellular carcinoma (HCC) metastasis are not completely understood. Materials and methods Exosomes derived from hepatoma cell lines with different invasion characteristics. Exosome characteristics, cell migration and invasion, and effects on major signal transduction pathways deregulated in cancer cells were analyzed by transmission electron microscopy (TEM), wound-healing assay, Trans-well invasion assay and Western blot-based assays, respectively. Moreover, exosomes effects on tumor metastasis in vivo were investigated by subcutaneous transplantation tumor model of athymic nude mice. Results Exosomes derived from hepatoma cells can promote the migration and invasion of recipient cells, induce the decrease of E-cadherin expression, increase the expression of Vimentin and promote epithelial-mesenchymal transition (EMT) in cells. Moreover, highly invasive hepatoma-cells-derived exosomes effects are stronger than low-invasive hepatoma cells and normal liver cells exosomes. Mechanistic studies showed that the biological alterations in recipient HCC cells treated with MHCC97H and MHCC97L-derived exosomes were caused by inducing EMT via TGF-β/Smad signaling pathway. In vivo experiments also suggest that highly invasive hepatoma cells derived exosomes are more likely to promote lung metastasis of HCC in nude mice. Conclusion Our results reveal the important role of tumor-derived exosomes in the migration and invasion of recipient cells and exosomes may be the novel therapeutic and prognostic targets for HCC patients.

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Exosomes derived from HCC cells with different invasion characteristics mediated EMT through TGF-β/Smad signaling pathway

Comparison of Laparoscopic and Open Approach in Treating Gallbladder Cancer.

In papillary thyroid cancer (PTC) patients, cervical lymph node metastases are common, which disseminate sequentially from the central neck to the lateral neck. However, there is also a chaotic pattern of lymph node metastasis occasionally. In this study, we summarized 653 PTC patients who underwent thyroidectomy and central lymph node dissection with or without lateral lymph node dissection from two hospitals to investigate the pattern and risk factors of lateral lymph node metastasis (LLNM) and skip metastasis. LLNM was significantly associated tumor size > 1 cm, presence of extrathyroidal extension, tumors in the upper-lateral pole, and the number of metastatic lymph nodes in the central compartment. The frequency of skip metastasis was 22.5% (20 of 89 patients). Multivariate analyses showed tumor size ≤ 1 cm, and tumors in the upper-lateral pole were separately and independently associated with the risk of skip metastasis. Presence of LLNM affected the recurrence-free survival (RFS). RFS did not show the significantly difference between patients with LLNM and skip metastasis. Despite the low incidence of skip metastasis, attention should be paid to the possibility of LLNM even in the absence of central lymph node metastases. Besides, for patients with risk factors of LLNM or skip metastasis, detailed preoperative examination for the lateral compartment, especially the level III, is essential.

Jia-Wei Feng

Papers

Predictive factors for central lymph node and lateral cervical lymph node metastases in papillary thyroid carcinoma

Significance of multifocality in papillary thyroid carcinoma.

Exosomes derived from HCC cells with different invasion characteristics mediated EMT through TGF-β/Smad signaling pathway

Comparison of Laparoscopic and Open Approach in Treating Gallbladder Cancer.

Predictive Factors for Lateral Lymph Node Metastasis and Skip Metastasis in Papillary Thyroid Carcinoma