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Ex Vivo Expansion and Drug Sensitivity Profiling of Circulating Tumor Cells from Patients with Small Cell Lung Cancer

期刊: CANCERS, 2020; 12 (11)

Simple Summary Small cell lung cancer (SCLC) is an overly aggressive cancer characterized by rapid growth, early metastatic spread, and consequently reducing overall survival. As cancer manifestations can differ uniquely between various types, the rapid proliferation of circulating tumor cells (CTC) originating from SCLC was an adequate sample resource to aid the headway in our drug screening technique. With biomarker detection of liquid biopsy as an emerging tool to assist decision-making in personalized cancer pharmacotherapy. In this study, we developed a rapid and reproducible system for preclinical drug testing via the use of a unique CTCs expansion protocol. The expanded CTCs from SCLC formed multiple types of tumorsphere structures and expressed SCLC-specific tumor markers. The drug sensitivity assessment gathered from in vitro expansion of CTCs was able to generate positive clinical therapeutic outcomes. Thus, SCLC patient-derived CTC spheroids are a useful resource for biomarker development and drug sensitivity assessment providing "real-world" therapeutic response circumstances. Small cell lung cancer (SCLC) represents one of the most aggressive malignancies among cancer types. Not only tumor sample availability is limited, but also the ability for tumor cells to rapidly acquire drug resistance are the rate-limiting bottlenecks for overall survival in current clinical settings. A liquid biopsy capable of capturing and enriching circulating tumor cells (CTCs), together with the possibility of drug screening, is a promising solution. Here, we illustrate the development of a highly efficient ex vivo CTC expansion system based on binary colloidal crystals substrate. Clinical samples were enrolled from 22 patients with SCLC in the study. The CTCs were enriched and expanded from the collected peripheral blood samples. Expanded cells were analyzed for protein expression and observed for drug sensitivity with the use of immunofluorescence and ATP titer evaluation, respectively. Successful CTC spheroid proliferation was established after 4 weeks within 82% of all the collected peripheral blood samples from enrolled patients. Upon immunofluorescence analysis, the enriched cells showed positive markers for EpCAM, TTF-1, synaptophysin and negative for CD45. Additionally, the expanded CTCs demonstrated marked heterogeneity in the expression of E-cadherin and N-cadherin. In a preliminary case series, the drug sensitivity of patient-derived CTC to cisplatin and etoposide was studied to see the correlation with the corresponding therapeutic outcome. In conclusion, our study demonstrates that it is possible to efficiently expand CTCs from SCLC within a clinically relevant time frame; the biomarker information generated from enriched CTCs can assist the selection of effective drugs and improve disease outcome.

Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8(+) T Cells in Non-Melanoma Cancers Compared to Melanoma

期刊: CANCERS, 2020; 12 (11)

Simple Summary Human tumors are often infiltrated by T cells; however, it remains unclear what proportion of T cells infiltrating tumors are bystander and non-tumor specific. We have investigated qualitative characteristics of these tumor-infiltrating lymphocytes (TILs) based on their gene-expression in the tumor-microenvironment or on their response to autologous tumor cells in vitro. Despite a considerable inter-sample variability, we found the overall proportion of bystander (non-tumor reactive) TILs to be remarkably high. Importantly, we observed a higher proportion of bystander TILs in non-melanoma tumors, compared to melanoma. This study suggests that immunotherapeutic strategies, especially when applied to non-melanoma tumors, should be tailored to reinvigorate the small proportion of tumor-reactive T cells infiltrating the tumor-microenvironment. Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8(+) and CD4(+) TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8(+) and CD4(+) TIL responses were detected in over half of the patients in vitro, and greater CD8(+) TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4(+) TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8(+) and CD4(+) tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.

Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

期刊: CANCERS, 2020; 12 (11)

Simple Summary DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has recently attracted increasing attention due to the emerging novel functions in cancer. However, several fundamental questions, such as the underlying molecular basis for DNA-PKcs pleiotropy and biomarkers for DNA-PKcs inhibitor sensitivity, remain to be addressed. In this review, we elaborate an updated summary of the most recent progress in DNA-PKcs, with particular emphasis on the mechanisms of DNA-PKcs multifaceted roles in malignancy and potential stratification approaches towards DNA-PKcs-based precision cancer therapy. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key component of the DNA-PK complex that has a well-characterized function in the non-homologous end-joining repair of DNA double-strand breaks. Since its identification, a large body of evidence has demonstrated that DNA-PKcs is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis of cancer patients. Intriguingly, recent studies have suggested novel functions beyond the canonical role of DNA-PKcs, which has transformed the paradigm of DNA-PKcs in tumorigenesis and has reinvigorated the interest to target DNA-PKcs for cancer treatment. In this review, we update recent advances in DNA-PKcs, in particular the emerging roles in tumor metastasis, metabolic dysregulation, and immune escape. We further discuss the possible molecular basis that underpins the pleiotropism of DNA-PKcs in cancer. Finally, we outline the biomarkers that may predict the therapeutic response to DNA-PKcs inhibitor therapy. Understanding the functional repertoire of DNA-PKcs will provide mechanistic insights of DNA-PKcs in malignancy and, more importantly, may revolutionize the design and utility of DNA-PKcs-based precision cancer therapy.

Quantifying the Effect of Financial Burden on Health-Related Quality of Life among Patients with Non-Hodgkin's Lymphomas

期刊: CANCERS, 2020; 12 (11)

Simple Summary Financial burdens result from the growing out-of-pocket costs associated with cancer care to help patients regain physical and psychological health-related quality of life (HRQoL) are dramatically intensified. The aim of our study was to assess the association of HRQoL with financial burden using both subjective and objective methods among patients with non-Hodgkin's lymphoma (NHL) in China. A majority of the patients reported suffering moderate to high financial burdens. A significant relationship between increased financial burden and reduced HRQoL was identified. Patients tended to report a poorer HRQoL when using objective method than using subjective method to estimate financial burden. Medical professionals should involve patients and their families into the clinical decision making and provide them cost-effective plans. Objective: This study aimed to assess the association of health-related quality of life (HRQoL) with financial burden among patients with non-Hodgkin's lymphoma (NHL) in China. Methods: The data used for the analyses came from a nationwide survey to investigate the health status of patients with lymphomas in China. The EQ-5D and EORTC QLQ-C30 were used to assess the patients' HRQoL. The financial burden was calculated using both subjective and objective methods. The chi-squared test, Kruskal-Wallis one-way analysis of variance, ordinal least squared model, and Tobit regression model were used to estimate the relationship between financial burden and HRQoL. Results: Data from 1549 patients who reported living with 11 subtypes of NHL were elicited for our analysis. Approximately 60% of respondents reported suffering moderate to high financial burdens. A significant relationship between increased financial burden and reduced HRQoL scores, including the EQ-Index, physical, emotional, and social functioning, was identified. Compared with using an objective method to measure financial burden, patients with NHL indicated a poorer HRQoL when using a subjective method to measure financial burden. Conclusion: Medical professionals should select highly cost-effective treatments and ensure that patients understand the potential financial consequences of those treatments.

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice

期刊: CANCERS, 2020; 12 (11)

Simple Summary Recently, the antiprogestin activity of selective progesterone receptor (PR) modulator mifepristone (MF) has proven unsuccessful as a potential anti-cancer agent in various clinical trials. Herein, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-alpha promoter-driven SV40 T-antigen), as well as on the proliferation of two Leydig tumor cell lines. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Only the abundant membrane Pgrmc1 expression was found in LCTs, but no other classical Pgr or nonclassical membrane PRs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Our findings provide novel information that the use of MF as an anti-cancer agent should be considered with caution due to its potential PGRMC1 tumor-promoting pathway activation in cancers. The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-alpha promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Traceable/absent classical Pgr or nonclassical membrane PRs alpha, beta, gamma and Pgrmc2, but abundant membrane Pgrmc1 expression, was found in LCTs. MF did not activate glucocorticoid or androgen receptors in LCTs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Accordingly, MF and P4 induced PGRMC1 translocation into the nucleus and thereby stimulated the release of TGF beta 1 in LCT cells. MF and P4 treatments upregulated Tgfbr1, Tgfbr2, and Alk1 expression and stimulated TGF beta 1 release in LCT cells. Our findings provide novel mechanistic insights into the action of MF as a membrane PR agonist that promotes LCT growth through PGRMC1 and the alternative TGF beta 1 signaling pathway.

BH3 Mimetics for the Treatment of B-Cell Malignancies-Insights and Lessons from the Clinic

期刊: CANCERS, 2020; 12 (11)

Simple Summary B-cell malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and plasma cell dyscrasias, are significant contributors to cancer morbidity and mortality worldwide. The pathogenesis of many B-cell malignancies involves perturbations in the intrinsic pathway of apoptosis that allow cells to evade cell death. BH3 mimetics represent a class of anti-cancer agents that can restore the ability of cancer cells to undergo apoptosis. Venetoclax, a recently approved BH3 mimetic, has transformed the therapeutic landscape for CLL. Other BH3 mimetics are currently under development. This review summarizes the available data on existing BH3 mimetics and highlights both the rapidly expanding role of BH3 mimetics in the treatment of B-cell malignancies and the clinical challenges of their use. The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field.

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

期刊: CANCERS, 2020; 12 (11)

Simple Summary The unique characteristics of tumor energy metabolism (highly dependent on aerobic glycolysis, namely, the Warburg effect) make it an interesting and attractive target for drug discovery. Radio- and chemoresistance are closely associated with the Warburg effect. Lonidamine (LND), as a glycolytic inhibitor, although having low anticancer activity when used alone, exhibits selectivity to various tumors, and its adverse effects do not overlap when combined with other chemotherapeutic drugs. Therefore, LND may be very promising as a sensitizer of tumors to chemotherapeutic agents and physical therapies. This review summarizes the advance of LND in combination with chemotherapy and physical therapy over the past several decades, as well as the promising LND derivative adjudin (ADD). The underlying sensitizing mechanisms were also analyzed and discussed, which may contribute to an improved therapeutic effect in future clinical cancer treatment. Lonidamine (LND) has the ability to resist spermatogenesis and was first used as an anti-spermatogenic agent. Later, it was found that LND has a degree of anticancer activity. Currently, LND is known to target energy metabolism, mainly involving the inhibition of monocarboxylate transporter (MCT), mitochondrial pyruvate carrier (MPC), respiratory chain complex I/II, mitochondrial permeability transition (PT) pore, and hexokinase II (HK-II). However, phase II clinical studies showed that LND alone had a weak therapeutic effect, and the effect was short and reversible. Interestingly, LND does not have the common side effects of traditional chemotherapeutic drugs, such as alopecia and myelosuppression. In addition, LND has selective activity toward various tumors, and its toxic and side effects do not overlap when combined with other chemotherapeutic drugs. Therefore, LND is commonly used as a chemosensitizer to enhance the antitumor effects of chemotherapeutic drugs based on its disruption of energy metabolism relating to chemo- or radioresistance. In this review, we summarized the combination treatments of LND with several typical chemotherapeutic drugs and several common physical therapies, such as radiotherapy (RT), hyperthermia (HT), and photodynamic therapy (PDT), and discussed the underlying mechanisms of action. Meanwhile, the development of novel formulations of LND in recent years and the research progress of LND derivative adjudin (ADD) as an anticancer drug were also discussed.

AGTR1 Is Overexpressed in Neuroendocrine Neoplasms, Regulates Secretion and May Potentially Serve as a Target for Molecular Imaging and Therapy

期刊: CANCERS, 2020; 12 (11)

Simple Summary Clinical management of neuroendocrine neoplasms (NEN), especially of those low in target molecules such as somatostatin receptors, may benefit from the discovery of novel targets. This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in NEN cells and its cognate receptor AGTR1 as overexpressed in human small intestinal NEN. NEN cells with high AGTR1 expression exhibited cellular activation and secretion upon stimulation with ATII. AGTR1 ligand saralasin coupled to a fluorescent dye demonstrated tumor accumulation in an animal model of NEN. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for its potential use in diagnostic PET imaging and radioligand therapy. This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in neuroendocrine neoplasm (NEN) cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in small-intestinal (n = 71) NEN tissues compared to controls (n = 25). NEN cells with high AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and G alpha q inhibition. ATII also stimulated serotonin secretion from BON cells. AGTR1 ligand saralasin was coupled to a near-infrared fluorescent (NIRF) dye and tested for its biodistribution in a nude mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. NIRF imaging showed significantly higher uptake in BON tumors. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for translational chelator-based probes for diagnostic PET imaging and radioligand therapy.

Growth Factor Receptor Expression in Oropharyngeal Squamous Cell Cancer: Her1-4 and c-Met in Conjunction with the Clinical Features and Human Papillomavirus (p16) Status

期刊: CANCERS, 2020; 12 (11)

Simple Summary Growth factor expression is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Targeted therapy has a limited effect on the treatment of advanced stages due to evolving resistance mechanisms. The aim of this study was to assess the distribution of growth factor receptors in oropharyngeal squamous cell cancer (OPSCC) and evaluate their role in the context of the human papillomavirus status, prognosis and possible relevance for targeted therapy. Tissue microarrays of 78 primary OPSCC, 35 related lymph node metastasis, 6 distant metastasis and 9 recurrent tumors were manufactured to evaluate the expression of human epidermal growth factor receptor (EGFR/erbB/Her)1-4 and c-Met by immunohistochemistry. EGFR and c-Met are relevant negative prognostic factors especially in noxae-induced OPSCC. Thus, dual targeting of EGFR and c-Met could be a promising prospective target in OPSCC treatment. Frequent coexpression of assessed receptors represents a possible intrinsic resistance mechanism in targeted therapy. This study aimed to assess the distribution of growth factor receptors in oropharyngeal squamous cell cancer (OPSCC) and evaluate their role in the context of human papillomavirus (HPV) status, prognosis and potential relevance for targeted therapy. The protein expression of human epidermal growth factor receptor (Her)1-4 and c-Met were retrospectively assessed using semiquantitative immunohistochemistry on tissue microarrays and analyzed for correlations as well as differences in the clinicopathological criteria. Her1-4 and c-met were overexpressed compared to normal mucosa in 46%, 4%, 17%, 27% and 23%, respectively. Interestingly, most receptors were coexpressed. Her1 and c-Met were inversely correlated with p16 (p = 0.04; p = 0.02). Her2 and c-Met were associated with high tobacco consumption (p = 0.016; p = 0.04). High EGFR, Her3, Her4 and c-Met expression were associated with worse overall and disease-free survival (p <= 0.05). Furthermore, EGFR and c-Met expression showed raised hazard ratios of 2.53 (p = 0.02; 95% CI 1.24-5.18) and 2.45 (p = 0.02; 95% CI 1.13-5.35), respectively. Her4 was expressed less in distant metastases than in corresponding primary tumors and was correlated to a higher T category. EGFR and c-Met are relevant negative prognostic factors in OPSCC, independent of known clinicopathological parameters. We suggest dual targeting of EGFR and c-Met as a promising strategy for OPSCC treatment.

Cold Atmospheric Plasma: A Promising Controller of Cancer Cell States

期刊: CANCERS, 2020; 12 (11)

Simple Summary Cancer treatment is complicated by the distinct phenotypic attractor states in which cancer cells exist within individual tumors, and inherent plasticity of cells in transiting between these states facilitates the acquisition of drug-resistant and more stem cell-like phenotypes in cancer cells. Controlling these crucial transition switches is therefore critical for the long-term success of any cancer therapy. This paper highlights the most promising avenues for controlling cancer state transition events by cold atmospheric plasma (CAP) to enable the development of efficient tools for cancer prevention and management. The key switches in carcinogenesis can be used to halt or reverse cancer progression, and understanding how CAP can modulate these processes is critical for the development of CAP-based strategies for cancer prevention, detection and effective treatment. Rich in reactive oxygen and nitrogen species, cold atmospheric plasma has been shown to effectively control events critical to cancer progression; selectively inducing apoptosis, reducing tumor volume and vasculature, and halting metastasis by taking advantage of, e.g., synergies between hydrogen peroxide and nitrites. This paper discusses the efficacy, safety and administration of cold atmospheric plasma treatment as a potential tool against cancers, with a focus on the mechanisms by which cold atmospheric plasma may affect critical transitional switches that govern tumorigenesis: the life/death control, tumor angiogenesis and epithelial-mesenchymal transition, and drug sensitivity spectrum. We introduce the possibility of modeling cell transitions between the normal and cancerous states using cold atmospheric plasma as a novel research avenue to enhance our understanding of plasma-aided control of oncogenesis.

The Role of Long Non-Coding RNA NNT-AS1 in Neoplastic Disease

期刊: CANCERS, 2020; 12 (11)

Simple Summary Nicotinamide nucleotide transhydrogenase-antisense 1 (NNT-AS1), which is a newly-discovered long non-coding RNA (lncRNA), has been found to be dysregulated in a variety of neoplastic diseases. With the accumulation of studies on NNT-AS1 in recent years, the mechanism of NNT-AS1 and its significance for tumor occurrence and progression are constantly being updated and improved. Thus, this paper aims to summarize the abnormal expression of NNT-AS1 and its prognostic values in different neoplastic diseases. In addition, the detailed competing endogenous RNA networks and subsequent biology behaviors, as well as the role of NNT-AS1 in mediating cisplatin resistance are revealed in this paper. This review not only summarizes the past research of NNT-AS1, but also provides some ideas for future research in this field. Studies have shown that non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), play an important regulatory role in the occurrence and development of human cancer. Nicotinamide nucleotide transhydrogenase-antisense 1 (NNT-AS1) is a newly-discovered cytoplasmic lncRNA. Many studies have shown that it has abnormally-high expression levels in malignant tumors, but there are also a few studies that have reported low expression levels of NNT-AS1 in gastric cancer, breast cancer, and ovarian cancer. At present, the regulatory mechanism of NNT-AS1 as a miRNA sponge, which may be an important reason affecting tumor cell proliferation, invasion, metastasis, and apoptosis is being studied in-depth. In addition, NNT-AS1 has been found to be related to cisplatin resistance. In this review, we summarize the abnormal expression of NNT-AS1 in a variety of neoplastic diseases and its diagnostic and prognostic value, and we explain the mechanism by which NNT-AS1 regulates cancer progression by competing with miRNAs. In addition, we also reveal the correlation between NNT-AS1 and cisplatin resistance and the potential clinical applications of NNT-AS1.

Transforming Growth Factor-beta: A Multifunctional Regulator of Cancer Immunity

期刊: CANCERS, 2020; 12 (11)

Simple Summary Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that can restrict cancer onset but also promote cancer progression at late stages of cancer. The ability of TGF-beta in producing diverse and sometimes opposing effects relies on its potential to control different cellular signalling and gene expression in distinct cell types, and environmental settings. The tumour promoting role of TGF-beta is primarily mediated through its effects on the local tumour microenvironment (TME) of the cancer cells. In this review, we discuss the most recent research on the role and regulation of TGF-beta, with a specific focus on its functions on promoting cancer progression through targeting different immune cells in the TME as well as its therapeutic perspectives. Transforming growth factor-beta (TGF-beta) was originally identified as an anti-tumour cytokine. However, there is increasing evidence that it has important roles in the tumour microenvironment (TME) in facilitating cancer progression. TGF-beta actively shapes the TME via modulating the host immunity. These actions are highly cell-type specific and complicated, involving both canonical and non-canonical pathways. In this review, we systemically update how TGF-beta signalling acts as a checkpoint regulator for cancer immunomodulation. A better appreciation of the underlying pathogenic mechanisms at the molecular level can lead to the discovery of novel and more effective therapeutic strategies for cancer.

Biomimetic Upconversion Nanoparticles and Gold Nanoparticles for Novel Simultaneous Dual-Modal Imaging-Guided Photothermal Therapy of Cancer

期刊: CANCERS, 2020; 12 (11)

Simple Summary Multimodal imaging systems with high registration accuracy and molecular agents with highly specific targeting capacity are vital for imaging-guided theranostics of cancer. A novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as an imaging-guided photothermal therapy (PTT) was reported in this paper. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for intrinsic simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. The highly specific imaging-guided PTT efficacy was evaluated both in vitro and in vivo. All these results suggested our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics. Multimodal imaging-guided near-infrared (NIR) photothermal therapy (PTT) is an interesting and promising cancer theranostic method. However, most of the multimodal imaging systems provide structural and functional information used for imaging guidance separately by directly combining independent imaging systems with different detectors, and many problems arise when trying to fuse different modal images that are serially taken by inviting extra markers or image fusion algorithms. Further, most imaging and therapeutic agents passively target tumors through the enhanced permeability and retention (EPR) effect, which leads to low utilization efficiency. To address these problems and systematically improve the performance of the imaging-guided PTT methodology, we report a novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as a platform for PTT-based cancer theranostics. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. In vitro and in vivo evaluation of macrophage escape and active homologous tumor targeting were performed. Cancer cell membrane-coated nanoparticles (CC-NPs) displayed excellent immune evasion ability, longer blood circulation time, and higher tumor targeting specificity compared to normal PEGylated nanoparticles, which led to highly specific upconversion luminescence (UCL) imaging and PTT-based anti-tumor efficacy. The anti-cancer efficacy of the dual-modal imaging-guided PTT was also evaluated both in vitro and in vivo. Dual-modal imaging yielded precise anatomical and functional information for the PTT process, and complete tumor ablation was achieved with CC-AuNPs. Our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics.

LDOC1 Suppresses Microbe-Induced Production of IL-1 beta in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3 beta Axis

期刊: CANCERS, 2020; 12 (11)

Simple Summary Oral microbes often proliferate due to poor oral hygiene (POH). POH is associated with OSCC (oral squamous cell carcinoma). We investigated the role of LDOC1 in the production of IL-1 beta, an oncogenic proinflammatory cytokine in OSCC, induced by microorganisms in human oral cells. Candida albicans (CA) was detected in OSCC tissues. CA and the oral bacterium Fusobacterium nucleatum stimulate higher levels of IL-1 beta production in LDOC1-deficient OSCC cells than in LDOC1-expressing oral cells. CA SC5314 increased OSCC incidence in carcinogen-treated mice. Loss and gain of LDOC1 function resulted in increased and decreased, respectively, CA SC5314-induced IL-1 beta production. LDOC1 deficiency increased active pAkt(S473) upon SC5314 stimulation and inactive pGSK-3 beta(S9) phosphorylated by pAkt(S473). PI3K and Akt inhibitors and expression of constitutively active mutant GSK-3 beta(S9A) reduced the SC5314-stimulated IL-1 beta production in LDOC1-deficient cells. These results indicate that the PI3K/Akt/pGSK-3 beta signaling contributes to LDOC1-mediated inhibition of microbe-induced IL-1 beta production, suggesting LDOC1 may determine the role of oral microbes in POH-associated OSCC. Poor oral hygiene (POH) is associated with oral squamous cell carcinoma (OSCC). Oral microbes often proliferate due to POH. Array data show that LDOC1 plays a role in immunity against pathogens. We investigated whether LDOC1 regulates the production of oral microbe-induced IL-1 beta, an oncogenic proinflammatory cytokine in OSCC. We demonstrated the presence of Candida albicans (CA) in 11.3% of OSCC tissues (n = 80). CA and the oral bacterium Fusobacterium nucleatum stimulate higher levels of IL-1 beta secretion by LDOC1-deficient OSCC cells than by LDOC1-expressing oral cells. CA SC5314 increased OSCC incidence in 4-NQO (a synthetic tobacco carcinogen) and arecoline-cotreated mice. Loss and gain of LDOC1 function significantly increased and decreased, respectively, CA SC5314-induced IL-1 beta production in oral and OSCC cell lines. Mechanistic studies showed that LDOC1 deficiency increased active phosphorylated Akt upon CA SC5314 stimulation and subsequent inhibitory phosphorylation of GSK-3 beta(S9) by activated Akt. PI3K and Akt inhibitors and expression of the constitutively active mutant GSK-3 beta(S9A) significantly reduced the CA SC5314-stimulated IL-1 beta production in LDOC1-deficient cells. These results indicate that the PI3K/Akt/pGSK-3 beta signaling pathway contributes to LDOC1-mediated inhibition of oral microbe-induced IL-1 beta production, suggesting that LDOC1 may determine the pathogenic role of oral microbes in POH-associated OSCC.

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