APOBEC3B is an enzymatic source of molecular alterations in esophageal squamous cell carcinoma

Abstract

APOBEC3B belongs to the cytidine deaminase apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3) family of enzymes and induces C to T transitions of target DNA by cytidine deamination. Recently, several mutations in various cancers have been linked to APOBEC3B, suggesting a crucial role for this protein in carcinogenesis and cancer development. However, the significance of APOBEC3B in esophageal squamous cell carcinoma (ESCC) remains uncertain. In addition, the APOBEC3B immunoreactivity in cancer tissues is uncertain. Recently, we have demonstrated that PIK3CA mutation and the methylation level of long interspersed nucleotide element 1 (LINE-1) (a surrogate marker of global DNA methylation level) are prognostic markers and have crucial role on malignancy in ESCC patients. This study aims to clarify the impact of APOBEC3B on the clinical, pathological, and molecular features of ESCC. We evaluated APOBEC3B expression in ESCC and investigated the relationships among the immunoreactivity of APOBEC3B, clinical and pathological features, and the molecular features of ESCC (PIK3CA mutation, p53 expression, and LINE-1 methylation level). The immunoreactivity and mRNA level of APOBEC3B were significantly higher in cancer tissues than in noncancerous esophageal mucosae (P = 0.050). APOBEC3B expression was significantly correlated with PIK3CA mutation (P = 0.013), particularly with C to T transitions of PIK3CA (P = 0.041). Moreover, a high expression of APOBEC3B was significantly associated with LINE-1 hypomethylation (P = 0.027). Given the crucial roles of PIK3CA mutation and LINE-1 methylation levels, our findings might provide new insights into the biological mechanisms of ESCC tumorigenesis and progression.

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CD20-targeting immunotherapy promotes cellular senescence in B-cell lymphoma

The CD20-targeting monoclonal antibody Rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its co-administration with conventional anti-cancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which Rituximab exerts its anti-lymphoma activity are only partially understood. We show here that Rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biological properties, in established B-cell lymphoma cell lines as well as primary transformed B-cells. In addition, Rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound Adriamycin (a.k.a. Doxorubicin), and, to a lesser extent, by the antimicrotubule agent Vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response (DDR) signaling cascade triggered by Adriamycin. As the underlying pro-senescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to Rituximab, and, in turn, the ROS scavenger N-acetylcysteine (NAC) to largely abrogate Rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a Rituximab-containing treatment regimen, provide important mechanistic insights into the biological complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy.

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Paclitaxel-loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy

Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer mortality, with a median survival of 1-3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here we employed flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with Paclitaxel® and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to four months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), Paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound Paclitaxel (Abraxane®). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of polymersomes-paclitaxel in treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with polymersome-Paclitaxel improved the therapeutic index of drug over Paclitaxel-Cremophor and Abraxane®, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions.

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A potent HER3 monoclonal antibody that blocks both ligand-dependent and independent activities: differential impacts of PTEN-status on tumor response

Human epidermal growth factor receptor 3 (HER3/ERBB3) is a kinase-deficient member of the epidermal growth factor receptor (EGFR) family receptor tyrosine kinases (RTKs) that is broadly expressed and activated in human cancers. HER3 is a compelling cancer target due to its important role in activation of the oncogenic PI3K/AKT pathway. It has also been demonstrated to confer tumor resistance to a variety of cancer therapies, especially targeted drugs against EGFR and HER2. HER3 can be activated by its ligand (heregulin/HRG), which induces HER3 heterodimerization with EGFR, HER2 or other RTKs. Alternatively, HER3 can be activated in a ligand-independent manner through heterodimerization with HER2 in HER2-amplified cells. We developed a fully human monoclonal antibody (mAb) against HER3 (KTN3379) that efficiently suppressed HER3 activity in both ligand-dependent and independent settings. Correspondingly, KTN3379 inhibited tumor growth in divergent tumor models driven by either ligand-dependent or independent mechanisms in vitro and in vivo. Most intriguingly, while investigating the mechanistic underpinnings of tumor response to KTN3379, we discovered an interesting dichotomy in that PTEN-loss, a frequently occurring oncogenic lesion in a broad range of cancer types, substantially blunted the tumor response in HER2-amplified cancer, but not in the ligand-driven cancer. To our knowledge, this represents the first study ascertaining the impact of PTEN-loss on the anti-tumor efficacy of a HER3 mAb. KTN3379 is currently undergoing a Phase-1b clinical trial in patients with advanced solid tumors. Our current study may help us optimize patient selection schemes for KTN3379 to maximize its clinical benefits.

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Bone marrow-derived cells in ocular neovascularization: contribution and mechanisms

Abstract

Ocular neovascularization often leads to severe vision loss. The role of bone marrow-derived cells (BMCs) in the development of ocular neovascularization, and its significance, is increasingly being recognized. In this review, we discuss their contribution and the potential mechanisms that mediate the effect of BMCs on the progression of ocular neovascularization. The sequence of events by which BMCs participate in ocular neovascularization can be roughly divided into four phases, i.e., mobilization, migration, adhesion and differentiation. This process is delicately regulated and liable to be affected by multiple factors. Cytokines such as vascular endothelial growth factor, granulocyte colony-stimulating factor and erythropoietin are involved in the mobilization of BMCs. Studies have also demonstrated a key role of cytokines such as stromal cell-derived factor-1, tumor necrosis factor-α, as well as vascular endothelial growth factor, in regulating the migration of BMCs. The adhesion of BMCs is mainly regulated by vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and vascular endothelial cadherin. However, the mechanisms regulating the differentiation of BMCs are largely unknown at present. In addition, BMCs secrete cytokines that interact with the microenvironment of ocular neovascularization; their contribution to ocular neovascularization, especially choroidal neovascularization, can be aggravated by several risk factors. An extensive regulatory network is thought to modulate the role of BMCs in the development of ocular neovascularization. A comprehensive understanding of the involved mechanisms will help in the development of novel therapeutic strategies related to BMCs. In this review, we have limited the discussion to the recent progress in this field, especially the research conducted at our laboratory.

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Future options of anti-angiogenic cancer therapy

Abstract

In human patients, drugs that block tumor vessel growth are widely used to treat a variety of cancer types. Many rigorous phase 3 clinical trials have demonstrated significant survival benefits; however, the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients. Currently, it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients. In this article, we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.

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Long-term outcomes of a phase II randomized controlled trial comparing intensity-modulated radiotherapy with or without weekly cisplatin for the treatment of locally recurrent nasopharyngeal carcinoma

Abstract

Background

Salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC) is complicated and relatively limited. Radiotherapy, combined with effective concomitant chemotherapy, may improve clinical treatment outcomes. We conducted a phase II randomized controlled trial to evaluate the efficacy of intensity-modulated radiotherapy with concomitant weekly cisplatin on locally recurrent NPC.

Methods

Between April 2002 and January 2008, 69 patients diagnosed with non-metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group (n = 34) or radiotherapy alone group (n = 35). All patients received intensity-modulated radiotherapy. The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days (range 23–53 days). The concomitant chemotherapy schedule was cisplatin 30 mg/m² by intravenous infusion weekly during radiotherapy.

Results

The median follow-up period of all patients was 35 months (range 2–112 months). Between concomitant chemoradiotherapy and radiotherapy groups, there was only significant difference in the 3-year and 5-year overall survival (OS) rates (68.7% vs. 42.2%, P = 0.016 and 41.8% vs. 27.5%, P = 0.049, respectively). Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in stage rT3–4 (33.0% vs. 13.2%, P = 0.009), stages III–IV (34.3% vs. 13.2%, P = 0.006), recurrence interval >30 months (49.0% vs. 20.6%, P = 0.017), and tumor volume >26 cm³ (37.6% vs. 0%, P = 0.006).

Conclusion

Compared with radiotherapy alone, concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC, especially those with advanced T category (rT3–4) and stage (III–IV) diseases, recurrence intervals >30 months, and tumor volume >26 cm³.

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