The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor.

Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

Concordance between treatment recommendations provided by IBM Watson for Oncology and a multidisciplinary tumor board for breast cancer in China.

OBJECTIVE: Watson for Oncology (WFO), an artificial intelligence from IBM Corporation, can provide a treatment plan by analyzing patient's disease characteristics. The present study was performed to examine the concordance between treatment recommendations proposed by WFO and the multidisciplinary tumor board at our center. The aim was to explore the feasibility of using WFO for breast cancer cases in China and to ascertain the ways to make WFO more suitable for Chinese patients with breast cancer. METHODS: Data from 302 breast cancer patients treated at the Second Affiliated Hospital of Xi'an Jiaotong University between October 2016 and February 2018 was retrieved and retrospectively analyzed by WFO. The recommendations were divided into 'recommended', 'considered' and 'not recommended' groups. Results were considered concordant when oncologists' recommendations were categorized as 'recommended' or 'for consideration' by WFO. RESULTS: The concordance rate of 200 subjects with postoperative adjuvant therapy was 77%. However, the rate was 27.5% in the remaining 102 cases with metastatic disease receiving either first-line or no treatment. Further analysis demonstrated that inconsistencies were mainly due to different choices of chemotherapy regimens. Subgroup study indicates that tumor stage, receptor status and age also had influences at the concordance rate. CONCLUSION: The results of this study suggest that WFO is a promising artificial intelligence system for the treatment of breast cancer. These findings can also serve as a reference framework for the inclusion of artificial intelligence in the ongoing medical reform in China.

Baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting PI3K/AKT pathway in vivo and vitro.

PURPOSE: Baicalein, a widely used Chinese herbal medicine, has shown anticancer effects on many types of human cancer cell lines. However, little is known about the underlying mechanism in human breast cancer cells. In this study, we examined the apoptotic and autophagic pathways activated following baicalein treatment in human breast cancer cells in vitro and in vivo. MATERIALS AND METHODS: In in vitro study, we used MTT and clone formation assay to confirm the inhibitory role of baicalein on proliferation of MCF-7 and MDA-MB-231 breast cancer cells. Apoptosis was detected employing Hoechst 33258 staining, JC-1 staining, and flow cytometry. Autophagy was monitored by acridine orange staining and transmission electron microscopy observation. Quantitative real-time PCR and Western blot analysis were employed to study the effects of baicalein on PI3K/AKT signaling components of MCF-7 and MDA-MB-231 breast cancer cells. In in vivo study, the effect of baicalein was tested with a breast cancer cells transplantation tumor model. RESULTS: Our study showed that baicalein has the potential to suppress cell proliferation, induce apoptosis and autophagy of breast cancer cells in vitro and in vivo. Furthermore, baicalein significantly downregulated the expression of p-AKT, p-mTOR, NF-κB, and p-IκB while enhancing the expression of IκB in MCF-7 and MDA-MB-231 cells. It also decreased the p-AKT/AKT and p-mTOR/mTOR ratios. CONCLUSION: Our study demonstrated that baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting the PI3K/AKT signaling pathway in vivo and vitro. Our study revealed that baicalein may be a potential therapeutic agent for breast cancer.

MiR-429 suppresses neurotrophin-3 to alleviate perineural invasion of pancreatic cancer.

Perineural invasion (PNI) potentially increases the risk of relapse and abdominal pain in patients with pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms of PNI of PDAC is incompletely revealed. Our study aimed to investigate roles of miR-429 in modulating PNI in PDAC. We found that miR-429 was downregulated in PDAC cancer tissues and was profoundly decreased in tissues with PNI. It was reduced in nine of the ten examined pancreatic cancer cell lines. MiR-429 mimics restored its cellular expressions in MIA PaCa-2 and BxCP3 cells and significantly suppressed cell viability and invasion of the cancer cells. The online bioinformatic software predicted that neurotrophin-3 (NT-3) was a potential target gene of miR-429. It was showed that NT-3 mRNA elevated in PC cancer tissues, especially in patients presenting PNI. MiR-429 upregulation substantially suppressed the NT-3 mRNA and secretion in cancer cells. Also, the dual luciferase reporter assays confirmed the interaction between miR-429 and NT-3. When co-culturing the two PDAC cells with PC-12 cells, the invaded cell counts significantly increased comparing with the sole culture of cancer cells. However, miR-429 mimic transfection or NT-3 blocking retarded the cancer invasion in the co-culture system. Besides, we found that cancer cells conditioned medium (CM) treatment significantly increased the neurite outgrowth percentage in PC-12 cells, which was suppressed by culturing with CM from miR-429 mimics-transfected cells. In the CM cultured PC-12 cells, NT-3 receptor TrkC as well as pain-related proteins TRPV1 and TRPV2 significantly elevated. Collectively, miR-429 potentially suppressed neurotrophin-3 to alleviate PNI of PDAC.

Baicalein suppress EMT of breast cancer by mediating tumor-associated macrophages polarization.

Tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment and play an important role in cancer progression. Baicalein has a wide range of pharmacological properties. This study explores the potential effect of baicalein on macrophages polarization and epithelial-mesenchymal transition (EMT) of breast cancer. Co-culture system was established to evaluate the interaction between TAMs and breast cancer cells. Then the role of baicalein in modulating TAMs function was assessed. Finally, breast cancer mouse model was established to study the underlying mechanism. In vitro experiments showed that co-culture with M2 macrophages significantly enhanced EMT of both MDA-MB-231 and MCF-7 breast cancer cells. Baicalein could regulate polarization of M2 and attenuate TGF-ß1 secretion. In vivo experiments showed that compared with the MDA-MB-231 + M2 group, tumor growth and metastasis of baicalein + MDA-MB-231 + M2 group was significantly inhibited, with smaller tumor size and decreased lung metastasis lesions. Our findings suggest that the regulation of TAMs may be a novel mechanism underlying the anti-tumor effects of baicalein in breast cancer.

Tumor-infiltrating lymphocytes are associated with ß-catenin overexpression in breast cancer.

BACKGROUND: Inhibition of lymphocytes infiltration and activity may impair antitumor immune response and limit treatment responsiveness. Wnt/ß-catenin pathway has been suggested to contribute to immune evasion in tumor by suppressing the function of immune cells and excluding T cell infiltration. However, the effects of Wnt/ß-catenin on TILs recruitment remain controversial. OBJECTIVE: We aimed to investigate whether intratumoral Wnt/ß-catenin signaling could affect the lymphocyte infiltration in breast cancer. METHODS: The distribution of stromal TILs, CD8+ and FOXP3+ TIL subsets, and the expression of ß-catenin were separately assessed on consecutive sections of 96 breast cancer specimens. RESULTS: Both stromal infiltrated TILs and ß-catenin expression were upregulated in hormone receptor negative HER2-enriched and TNBC subtypes. Furthermore, high levels of stromal TILs as well as CD8+ or FOXP3+ TIL subsets were associated with ß-catenin overexpression by breast cancer, respectively. CONCLUSIONS: For the first time, we demonstrated that rather than excluding lymphocytes infiltration as reported in mela-noma, high levels of TILs were associated with ß-catenin overexpression in BC. Wnt/ß-catenin signaling may play a critical role in BC immunity, particularly in HER2-enriched and triple negative BC, and may serve as a potential target for regulating immune infiltrates in breast cancer.

Clinicopathological and prognostic significance of c-Met overexpression in breast cancer.

BACKGROUND: c-Met has been shown to promote organ development and cancer progression in many cancers. However, clinicopathological and prognostic value of c-Met in breast cancer remains elusive. METHODS: PubMed and EMBASE databases were searched for eligible studies. Correlation of c-Met overexpression with survival data and clinicopathological features was analyzed by using hazard ratio (HR) or odds ratio (OR) and fixed-effect or random-effect model according to heterogeneity. All statistical tests were two-sided. RESULTS: 32 studies with 8281 patients were analyzed in total. The c-Met overexpression was related to poor OS (overall survival) (HR=1.65 (1.328, 2.051)) of 18 studies with 4751 patients and poor RFS/DFS (relapse/disease free survival) (HR=1.53 (1.20, 1.95)) of 12 studies with 3598 patients. Subgroup analysis according to data source/methods/ethnicity showed c-Met overexpression was related to worse OS and RFS/DFS in Given by author group, all methods group and non-Asian group respectively. Besides, c-Met overexpression was associated with large tumor size, high histologic grade and metastasis. CONCLUSIONS: Our results showed that c-Met overexpression was connected with poor survival rates and malignant activities of cancer, including proliferation, migration and invasion, which highlighted the potential of c-Met as significant candidate biomarker to identify patients with breast cancer at high risk of tumor death.