The major cause of cancer-associated mortality is tumor metastasis, a disease that is far from understood. Many studies have observed circulating tumor cells (CTCs) in patients' circulation systems, and a few latest investigations showed that CTC clusters have a potentially high capacity of metastasis. The capture and analysis of CTC clusters offer new insights into tumor metastasis and can facilitate the development of cancer treatments. We reviewed the research history of the CTC clusters, as well as the technologies used for detecting and isolating CTC clusters. In addition, we discuss the characteristics of CTC clusters and their roles in tumor dissemination. Clinical relevance of CTC clusters was also implicated in currently limited data. Moving forward, the next frontier in this field is to develop more efficient capture methods and decipher conundrums of characterization of CTC clusters. This will ultimately identify the clinical value of CTC clusters as a biomarker and therapeutic target.

Hepatocellular carcinoma (HCC) is a common cancer worldwide with a poor prognosis. Few strategies have been proven efficient in HCC treatment, particularly for those patients not indicated for curative resection or transplantation. Immunotherapy has been developed for decades for cancer control and is attaining more attention as a result of encouraging outcomes of new strategies such as chimeric antigen receptor T cells and immune checkpoint blockade. Right at the front of the new era of immunotherapy, we review the immunotherapy in HCC treatment, from basic research to clinical trials, covering anything from immunomodulators, tumor vaccines and adoptive immunotherapy. The mechanisms, efficacy and safety as well as the approach particulars are unveiled to assist readers to gain a concise but extensive understanding of immunotherapy of HCC.

Hostile microenvironment produced by abnormal blood vessels, which is characterized by hypoxia, low pH value and increasing interstitial fluid pressure, would facilitate tumor progression, metastasis, immunosuppression and anticancer treatments resistance. These abnormalities are the result of the imbalance of pro-angiogenic and anti-angiogenic factors (such as VEGF and angiopoietin 2, ANG2). Prudent use of anti-angiogenesis drugs would normalize these aberrant tumor vessels, resulting in a transient window of vessel normalization. In addition, use of cancer immunotherapy including immune checkpoint blockers when vessel normalization is achieved brings better outcomes. In this review, we sum up the advances in the field of understanding and application of the concept of tumor vessels normalization window to treat cancer. Moreover, we also outline some challenges and opportunities ahead to optimize the combination of anti-angiogenic agents and immunotherapy, leading to improve patients’ outcomes.

BackgroundLung cancer is the most common type of cancer throughout the world, and the morbidity of lung cancer is continuously increasing. Patients with advanced lung cancer often cannot tolerate chemoradiotherapy. The decrease of the expression of miRNA-21 can be used as an indicator of the therapeutic effect of lung cancer. In this study, the effect of Kanglaite injection on serum miRNA-21 in patients with advanced lung cancer was investigated, providing reliable and important evidences.Material/MethodsFrom March 2016 to March 2017, 120 patients with advanced lung cancer were examined; we collected detailed information and serum samples. The patients were treated by intravenous drip of Kanglaite, which was provided by Zhejiang Kanglaite Pharmaceutical Co., Ltd., China. We administered 200 ml intravenous drip once per day for a total of 21 days. Serum samples were collected from patients after treatments. In this study, 4 observation indexes were considered – KPS (Karnofsky performance score, KPS), body weight, adverse effects, and miRNA-21 level – evaluated before and after the Kanglaite treatment.ResultsAmong 120 patients with advanced lung cancer, the KPS of 75 patients (63.1%) was increased after the treatment, and body weight was increased by 55.9%. In addition, serum miRNA-21 level after the Kanglaite treatment was 2.45±0.15, which was significantly lower than before treatment (3.87±0.54), (P<0.05).ConclusionsThe effect of Kanglaite injection on serum miRNA-21 in patients with advanced lung cancer was shown to significantly reduce the expression of miRNA-21, providing objective evidence for the effect of Kanglaite injection in patients with advanced lung cancer.

Histone deacetylase inhibitors (HDACIs) cause oncogene-transformed mammalian cell death. Our previous study indicated that HDACIs activate forkhead box O1 (FOXO1) and induce autophagy in liver and colon cancer cells. However, whether FOXO1 is involved in HDACI-mediated oncogene-transformed mammalian cell death remains unclear. In the present study, H-ras transformed MCF10A cells were used to investigate the role of FOXO1 in this pathway. Results showed that trichostatin A (TSA), a HDACI, activated apoptosis in MCF10A-ras cells, but not in MCF10A cells. Furthermore, TSA activated FOXO1 via P21 upregulation, whereas the knockdown of FOXO1 reduced TSA-induced cell death. In addition, TSA induced autophagy in MCF10A and MCF10A-ras cells by blocking the mammailian target of rapamycin signaling pathway. Furthermore, autophagy inhibition lead to higher MCF10A-ras cell death by TSA, thus indicating that autophagy is essential in cell survival. Taken together, the present study demonstrated that TSA causes oncogene-transformed cell apoptosis via activation of FOXO1 and HDACI-mediated autophagy induction, which served as important cell survival mechanisms. Notably, the present findings imply that a combination of HDACIs and autophagy inhibitors produce a synergistic anticancer effect.

Abstract. Metastasis is the major cause of mortality in patients with malignancies; however, the mechanisms of tumor cell dissemination and metastasis formation are obscure. Circulating tumor cells (CTCs) are believed to be a critical step for distant metastasis and are associated with a poor patient prognosis. The precise processes of metastasis formation from CTCs are vague. In the present study, we hypothesize that two CTC cluster-based mechanisms of tumor cell inoculation in ectopic organs may be viable: i) Formation of a micro-cancer embolus due to interception of CTC clusters by small vessels; and ii) formation of micrometastasis in an extravasation-dependent or -independent manner. Pathological evidence of micro-cancer emboli is critical for the verifications of this hypothesis. If proved true, this hypothesis will provide a novel perspective for cancer metastasis and has valuable clinical implications.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fifth leading cause of cancer-related death worldwide. Novel prognostic biomarkers are urgently needed for patients with HCC. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) overexpression may promote tumor metastasis in HCC. However, few studies investigate the prognosis predictive role of LGR5 in patients with HCC. Herein, we aimed to examine the expression level of LGR5 in tumors and its correlation with clinical characteristics and survivals of patients with HCC. LGR5 expression in tumor specimens and adjacent tissue resected from 66 patients were detected by immunohistochemistry. The results showed that the expression of LGR5 was markedly higher in HCC than in normal adjacent tissues (P = .006). High expression of LGR5 was significantly correlated with later disease stage (P = .009). In addition, high LGR5 expression was remarkably correlated with short overall survival than those with low LGR5 expression (P < .05). The median overall survival of patients with high LGR5 expression was 12 months, whereas that of patients with low LGR5 expression was still not reached (longer than 70 months). Notably, in our limited cases, we did not detect any difference in tumor size, lymphatic invasion, or metastasis in patients with high or low expression of LGR5. In conclusion, high protein level of LGR5 was associated with poor prognosis of these patients. LGR5 appears to be a valuable prognostic predictor clinically and a potential target in HCC therapy.

The combination of gene therapy and radiation is a promising new treatment for cancer. This study aimed to clarify the synergistic effect of targeted oncolytic adenovirus (radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand) and radiotherapy on colorectal cancer cells and elucidate the mechanisms of the underlying antitumor activity. Viability, cell cycle status, and apoptosis of treated colorectal cancer cells were determined via MTT and flow cytometric assays. The molecular mechanism underlying apoptotic pathway activation was elucidated through Western blot analysis of caspase-8, caspase-3, and PARP proteins. Combination treatment with radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand and radiotherapy displayed significantly greater antitumor activity than either of the monotherapies. The primary mechanism behind the antitumor activity in the SW480 and Lovo colorectal cancer cell lines was apoptosis induction through the caspase pathway and G1 phase arrest. In an SW480 xenograft model of colorectal cancer, the combination therapy achieved a significantly greater reduction in tumor volume than the monotherapies. Overall, in this study, we demonstrate that the oncolytic radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand construct can sensitize human colorectal cancer cells to radiation-induced apoptosis both in vitro and in vivo. Therefore, our findings point toward a novel synergistic approach to colorectal cancer treatment.