Optimal Courses of Chemotherapy Combined with Radiotherapy for Low-Risk Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Propensity Score Matching Analysis.

PURPOSE: This retrospective study compared effectiveness between ≤4 cycles and ≥5 cycles of L-asparaginase/pegaspargase-based chemoradiation in newly diagnosed low-risk extranodal natural killer/T-cell lymphoma (ENKTL), nasal type classified according to the Prognostic Index of Natural Killer (PINK) lymphoma model. PATIENTS AND METHODS: Patients were categorized into ≤4-cycle (2-4 chemotherapy cycles, n = 166) and ≥5-cycle groups (5-6 cycles, n = 86). Propensity score matching analysis was used to reduce potential confounding bias between the two groups. Treatment responses, adverse events, and survival outcomes between the two groups were analyzed. RESULTS: No matter before or after matching (65 in the ≤4-cycle group, 65 in the ≥5-cycle group), response rates and survival outcomes were similar between the ≤4-cycle and ≥5-cycle groups. Incidences of grade 1-2 anemia and transaminase elevation were higher in the ≥5-cycle group. After matching, for stage IE disease, there were no differences in response rates and survival outcomes between the two groups. For stage IIE disease, the complete response rate was higher in the ≥5-cycle group (72.4% vs 92.6%, p = 0.049), and the 3-year overall survival (65.5% vs 85.2%, p = 0.024) and 3-year progression-free survival (58.6% vs 81.5%, p = 0.027) rates were significantly extended in the ≥5-cycle group. CONCLUSION: When chemoradiotherapy strategies with L-asparaginase/pegaspargase-based regimens are applied to modern low-risk ENKTL patients classified according to the PINK model, it may be better to moderately extend chemotherapy courses in patients with stage IIE disease.

Diallyl disulfide inhibits colon cancer metastasis by suppressing Rac1-mediated epithelial-mesenchymal transition.

BACKGROUND: Prevention of epithelial-mesenchymal transition (EMT) provides a novel treatment strategy for tumor metastasis. Our previous studies have shown that diallyl disulfide (DADS) inhibits Ras related C3 botulinum toxin substrate1 (Rac1) expression, being a potential agent that suppresses migration and invasion of colon cancer cells. The study provides information on the underlying mechanisms. METHODS: The expression of Rac1 and EMT markers (vimentin, N-cadherin and E-cadherin) in colon cancer samples was detected. Colon cancer cell lines treated with or without DADS were used to examine EMT markers, Rac1 and its related molecules. Various cell functions related to metastasis were performed in vitro, and further confirmed in vivo. RESULTS: Rac1 was highly expressed in colon cancer, and associated with aberrant expression of EMT markers and poor prognosis. Rac1 overexpression induced cell migration and invasion in vitro and metastasis in vivo with down-regulation of E-cadherin and up-regulation of N-cadherin, vimentin, and snail1, whereas inhibition of Rac1 impaired the oncogenic function. DADS suppressed Rac1 expression and activity via inhibition of PI3K/Akt pathway, thus suppressing EMT and invasion and migration of colon cancer cells. The tumor inhibition of DADS was enhanced by knockdown of Rac1, but antagonized by overexpression of Rac1. We further found that DADS blocked EMT via targeting the Rac1-mediated PAK1-LIMK1-Cofilins signaling. CONCLUSION: Rac1 is a potential target molecule for the inhibitory effect of DADS on EMT and invasion and metastasis of colon cancer cells.

LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma.

Long-palate, lung and nasal epithelium clone 1 (LPLUNC1) is a tumour suppressor gene in nasopharyngeal carcinoma (NPC), and low expression of LPLUNC1 is associated with poor prognosis. Our previous study showed that LPLUNC1 upregulates Prohibitin 1 (PHB1), a pleiotropic protein that functions as a tumour suppressor gene in various cancers. Low expression of PHB1 was also found to be associated with the poor prognosis of NPC patients. However, the mechanisms by which LPLUNC1 upregulates PHB1 and the potential role of PHB1 in NPC are unclear. Here, we found that LPLUNC1 stabilised PHB1 by inhibiting PHB1 ubiquitination, which is mediated by E3 ligase TRIM21. LPLUNC1 competitively impaired the binding of PHB1 to TRIM21 due to its stronger binding affinity to PHB1, suppressing the ubiquitination of PHB1. Therefore, our study indicates that PHB1 acted as a tumour suppressor gene by inhibiting NF-κB activity. Depletion of PHB1 significantly attenuated the anti-tumour effects of LPLUNC1 in NPC cells, and the inhibitory effect of LPLUNC1 on NF-κB activity was thus reversed. Together, our findings revealed a novel mechanism underlying the anticancer effect of LPLUNC1 and clarified that PHB1 may represent a novel, promising candidate tumour suppressor gene in NPC, with potential therapeutic target value.

Cancer stem cells in progression of colorectal cancer.

Colorectal cancer is one of the most common cancers worldwide with high mortality. Distant metastasis and relapse are major causes of patient death. Cancer stem cells (CSCs) play a critical role in the metastasis and relapse of colorectal cancer. CSCs are a subpopulation of cancer cells with unique properties of self-renewal, infinite division and multi-directional differentiation potential. Colorectal CSCs are defined with a group of cell surface markers, such as CD44, CD133, CD24, EpCAM, LGR5 and ALDH. They are highly tumorigenic, chemoresistant and radioresistant and thus are critical in the metastasis and recurrence of colorectal cancer and disease-free survival. This review article updates the colorectal CSCs with a focus on their role in tumor initiation, progression, drug resistance and tumor relapse.

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells.

BACKGROUND/AIMS: Chronic inflammation plays an important role in the initiation and progression of gastric cancer (GC). However, the role and relationship of activated macrophages with gastric mucous epithelium cells in initiating and maintaining the inflammatory process during gastric carcinogenesis remains unclear. METHODS: The tumour associated macrophages (TAMs) density of gastric cancer was characterized by immunohistochemistry, and the relationship between macrophages and gastric epithelium cells was analysed using an in vitro culture system that imitates the inflammatory microenvironment. The production of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). MTT assays, Western blotting, qRT-PCR, and luciferase reporter assays were used to detect the effects of cell proliferation, as well as the NF-κB and STAT3 signalling pathways. RESULTS: TAMs infiltrated with a high intensity in GC and were significantly correlated with histology grade (P = 0.012), metastasis (P = 0.001), TNM stage (P = 0.002), and poor prognosis in patients (PFS, P = 0.005; OS, P = 0.028). In addition, IL-6 and IL-8 were elevated in the serum of GC patients and significantly promoted the growth of GC. The exposure of BGC823 gastric cancer cells to a conditioned medium from LPS-treated D-THP-1 cells significantly induced the production of TNF-α, IL-6, IL-1ß and IL-8 (P< 0.01). LPS and LPS-treated D-THP-1-conditioned media promoted gastric cancer cell proliferation and triggered the significant activation of NF-κB and STAT3 with a concomitant degradation of IκBα and an increase in JAK2 phosphorylation (P < 0.05). Moreover, gastric cancer cells markedly expressed cell membrane LPS receptors, such as TLR1, TLR4, TLR6, CD14 and MD2. CONCLUSIONS: TAMs are closely associated with the growth of GC and prognosis in GC patients. GC cells may directly sustain and amplify the local pro-inflammatory response upon encountering activated macrophages and LPS via NF-κB and STAT3 signalling pathways, thereby promoting tumour progression.

Role of the NFκB-signaling pathway in cancer.

Cancer is a group of cells that malignantly grow and proliferate uncontrollably. At present, treatment modes for cancer mainly comprise surgery, chemotherapy, radiotherapy, molecularly targeted therapy, gene therapy, and immunotherapy. However, the curative effects of these treatments have been limited thus far by specific characteristics of tumors. Abnormal activation of signaling pathways is involved in tumor pathogenesis and plays critical roles in growth, progression, and relapse of cancers. Targeted therapies against effectors in oncogenic signaling have improved the outcomes of cancer patients. NFκB is an important signaling pathway involved in pathogenesis and treatment of cancers. Excessive activation of the NFκB-signaling pathway has been documented in various tumor tissues, and studies on this signaling pathway for targeted cancer therapy have become a hot topic. In this review, we update current understanding of the NFκB-signaling pathway in cancer.

Exosomes in Nasopharyngeal Carcinoma.

Exosomes are nanosized (30-100nm) membrane microvesicles secreted through a complex cellular process. Exosomes contain a variety of bioactive molecules, such as proteins, microRNAs(miRNAs or miRs) and long non-coding RNAs (lncRNAs), playing an important role in the cell-to-cell substance transportation and signal transduction. Nasopharyngeal carcinoma-related exosomes (NPC-Exo) have been identified in circulating blood and contribute to tumor cell proliferation, angiopoiesis, and immune tolerance through remodeling of tumor microenvironment (TME). Nasopharyngeal carcinoma-related exosomes may also induce epithelial-mesenchymal transition (EMT), thus promoting tumor metastasis and chemoradioresistance. Clinically, the exosomes may serve as novel biomarkers for diagnosis and targeted therapies of nasopharyngeal carcinoma. This review article updates the understanding of exosomes in nasopharyngeal carcinoma(NPC).