Search

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18–encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt−DVL3−β-catenin signaling axis. Functional studies verified that the ASPM-I1–regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1–mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target.Significance:ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability.

This file contains Supplementary figures S1-S6

This file contains Supplementary Tables 1-3

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18–encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt−DVL3−β-catenin signaling axis. Functional studies verified that the ASPM-I1–regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1–mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target.Significance:ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability.

For resectable esophageal cancer (EC), it remains controversial whether to place percutaneous endoscopic gastrostomy (PEG) before the curative surgery to provide nutritional support during the neoadjuvant therapy. To compare surgical outcomes for patients who received preoperative PEG and those without PEG placement (No-PEG) insertion prior to surgery in a potentially operable EC. A comprehensive literature search was conducted to identify randomized and non-randomized studies comparing PEG and No-PEG groups. Four retrospective studies with a total number of 1,027 patients were identified and included in this meta-analysis. The differences in anastomotic leakage, anastomotic stricture, morbidity, pulmonary complications, wound infection, and hospital stay were not statistically significant between the two groups. Operation time was significantly shorter in the PEG group. There was no PEG-related gastric conduit failure and no leak from the PEG site in the PEG group. We conclude preoperative PEG for resectable EC is a safe procedure with no adverse effect on the gastric tube construction and anastomosis, it can be selectively inserted for EC patients with marked weight loss and malnutrition or those at risk of developing malnutrition during neoadjuvant therapy.

Simple Summary TNF-α is considered to be a potential therapeutic drug for cancer, but the systemic toxicity problem still exists in clinical use. MCPIP1 plays a crucial role in anti-inflammatory and anti-viral contexts, as well as in the inhibition of cell growth. This study aims to investigate the roles of MCPIP1 in TNF-α-treated cells and their underlying molecular mechanisms. MCPIP1 was found to enhance TNF-α-induced apoptosis by activating the caspase cascade, and pan-caspase inhibitor and the caspase-1/-4 inhibitor could reverse TNF-α/MCPIP1-mediated apoptosis. MCPIP1 was first identified with cleavage site of caspase-1/-4 and could be cleaved during apoptosis. Downregulation of NF-κB activation and a caspase-8 inhibitor, cFLIP, were associated with TNF-α/MCPIP1-mediated apoptosis. Abstract Monocyte chemoattractant protein-1-induced protein 1 (MCPIP1) is rapidly produced under proinflammatory stimuli, thereby feeding back to downregulate excessive inflammation. In this study, we used the stable, inducible expressions of wild-type (WT) MCPIP1 and an MCPIP1-D141N mutant in T-REx-293 cells by means of a tetracycline on (Tet-on) system. We found that WT MCPIP1 but not MCPIP1-D141N mutant expression dramatically increased apoptosis, caspase-3, -7, -8, and -9 activation, and c-Jun N-terminal kinase (JNK) phosphorylation in TNF-α-treated cells. The pan-caspase inhibitor, z-VAD-fmk, and the caspase-1 inhibitor, z-YVAD-fmk, but not the JNK inhibitor, SP600125, significantly reversed apoptosis and caspase activation in TNF-α/MCPIP1-treated cells. Surprisingly, MCPIP1 itself was also cleaved, and the cleavage was suppressed by treatment with the pan-caspase inhibitor and caspase-1 inhibitor. Moreover, MCPIP1 was found to contain a caspase-1/-4 consensus recognition sequence located in residues 234~238. As expected, the WT MCPIP1 but not the MCPIP1-D141N mutant suppressed NF-κB activation, as evidenced by inhibition of IκB kinase (IKK) phosphorylation and IκB degradation using Western blotting, IKK activity using in vitro kinase activity, and NF-κB translocation to nuclei using an immunofluorescence assay. Interestingly, MCPIP1 also significantly inhibited importin α3 and importin α4 expressions, which are major nuclear transporter receptors for NF-κB. Inhibition of NF-κB activation further downregulated expression of the caspase-8 inhibitor, cFLIP. In summary, the results suggest that MCPIP1 could enhance the TNF-α-induced apoptotic pathway through decreasing NF-κB activation and cFLIP expression.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment‐resistant malignancy. The lack of pathway‐informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle‐like microcephaly‐associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform‐specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM‐iII are variably upregulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM‐iI is exclusively localized to the cortical cytoplasm of PDAC cells, while ASPM‐iII is predominantly expressed in cell nuclei. Mechanistically, ASPM‐iI co‐localizes with disheveled‐2 and active β‐catenin as well as the stemness marker aldehyde dehydrogenase‐1 (ALDH‐1), and its expression is indispensable for the Wnt activity, stemness, and the tumorigenicity of PDAC cells. By contrast, ASPM‐iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM‐iI and ASPM‐iII displays considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM‐iI was prognostically significant; it outperformed ALDH‐1 staining and clinico‐pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the way for the development of therapies targeting this novel oncoprotein. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified. The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated. Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on β-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1–ASPM), protein–protein interactions (ASPMiI–DVL3–β-catenin), and nuclear translocation (FOXM1–β-catenin). This study illuminates a novel Wnt- and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1highASPMiIhigh GC with potential to guide Wnt- and stemness-related diagnostics and therapies.

Recurrent and hormone-refractory prostate cancer (PCA) exhibits aggressive behaviors while current therapeutic approaches show little effect of prolonging the survival of patients with PCA. Thus, a deeper understanding of the patho-molecular mechanisms underlying the disease progression in PCA is crucial to identify novel diagnostic and/or therapeutic targets to improve the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here, we report that a novel Wnt co-activator ASPM (abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation by augmenting the Wnt-β-catenin signaling in PCA. ASPM expression is incrementally upregulated in primary and metastatic PCA, implicating its potential role in PCA progression. Consistently, downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH+ CSCs and inhibited cancer stemness and tumorigenicity. Mechanistically, ASPM interacts with disheveled-3 (Dvl-3), a cardinal upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing its protein stability and enabling the Wnt-induced β-catenin transcriptional activity in PCA cells. In keeping with the role of ASPM as a CSC-regulator, ASPM co-localizes with ALDH in PCA tissues and its expression exhibits high intra-tumoral heterogeneity. The proportion of high-ASPM-expressing cells in the tumor inversely correlates with the relapse-free survival of PCA patients. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of Wnt signaling and cancer stemness in PCA, which has important clinical and therapeutic significance.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating and highly aggressive malignancy. Existing therapeutic strategies only provide a small survival benefit in patients with PDAC. Laboratory and clinical research have identified various populations of stem-cell-like cancer cells or cancer stem cells (CSCs) as the driving force of PDAC progression, treatment-resistance, and metastasis. Whilst a number of therapeutics aiming at inhibiting or killing CSCs have been developed over the past decade, a series of notable clinical trial setbacks have led to their deprioritization from the pipelines, triggering efforts to refine the current CSC model and exploit alternative therapeutic strategies. This review describes the current and the evolving models of pancreatic CSCs (panCSCs) and the potential factors that hamper the clinical development of panCSC-targeted therapies, emphasizing the heterogeneity, the plasticity, and the non-binary pattern of cancer stemness, as well as the desmoplastic stroma impeding drug penetration. We summarized novel and promising therapeutic strategies implicated by the works of our groups and others’ that may overcome these hurdles and have shown efficacies in preclinical models of PDAC, emphasizing the unique advantages of targeting the stroma-engendered panCSC-niches and metronomic chemotherapy. Finally, we proposed feasible clinical trial strategies and biomarkers that can guide the next-generation clinical trials.

Chemotherapy (C/T) drugs are usually administered to cancer patients every few weeks at a high, “maximum tolerated” dose (MTD). Though this approach kills the majority of tumor cells, it often spares a small number of stem-like cancer cells (CSCs) that subsequently give rise to new tumors. Moreover, these recurring tumors are often more aggressive and able to metastasize to other tissues, in part because high doses of C/T drugs also affect cells in the stromal tissue that surrounds tumors, including carcinoma-associated fibroblasts (CAFs) and immune cells. Many human solid tumors are characterized by a pronounced stromal reaction characterized by a desmoplastic response produced by CAFs as well as an extensive infiltration by immunosuppressive cell populations such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Importantly, both the tumor epithelium and adjacent stroma respond to systemic C/T and a therapy-modified stroma can deleteriously influence treatment efficacy. Recently, we have demonstrated in assorted mouse tumor models that traditional C/T using the MTD regimens of C/T agents such as cyclophosphamide, doxorubicin, gemcitabine, and paclitaxel could paradoxically render CAFs oncogenic through the stromal-epithelial ELR+-chemokine/CXCR-2 signaling axis, which expands CSCs, enhances tumor neovascularization, and induces immunosuppressive M2 subtype TAM infiltration, together leading to tumor recurrence and treatment refractoriness (Chan et al., J. Exp. Med 2016). By contrast, the same total accumulated dose of the C/T agents administered as a low-dose metronomic (LDM) regimen could largely prevent the therapy-induced stromal alterations and CSC expansion and thereby substantially enhance the treatment response. We subsequently showed that LDM C/T not only obviated the MTD-C/T-elicited CSC expansion but also attenuated the influx of the highly immunosuppressive granulocytic MDSCs, thereby potentiating immunotherapy such as anti-PD-1. We thus anticipate that, while pharmacologic inhibition of CXCR-2 has enhanced the antitumor efficacy of immune checkpoint blockade, LDM C/T may provide a clinically applicable alternative of enhancing immune surveillance in stroma-rich and T-cell inflamed tumors. Collectively, our studies provide compelling evidence and novel mechanistic insights into the unique benefit of LDM C/T on the tumor stroma. Given that MTD C/T exerts favorable influences on tumor stemness and immunity, it may better synergize with emerging CSC-targeted or immunotherapeutics than traditional MTD C/T to further enhance the therapeutic outcome of human solid tumors. Citation Format: Kelvin K. Tsai, Tze-sian Chan. Metronomic chemotherapy enhances immunotherapy by preventing stroma-induced immunosuppression [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A19.

Recurrent and hormone-refractory prostate cancer (PCA) exhibits aggressive behaviors while current therapeutic approaches show little effect of prolonging the survival of patients with PCA. Thus, a deeper understanding of the patho-molecular mechanisms underlying the disease progression in PCA is crucial to identify novel diagnostic and/or therapeutic targets to improve the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here, we report that a novel Wnt co-activator ASPM (abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation by augmenting the Wnt-β-catenin signaling in PCA. ASPM expression is incrementally upregulated in primary and metastatic PCA, implicating its potential role in PCA progression. Consistently, downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH

Background Patients with cytomegalovirus (CMV) colitis have increasingly been recognized among critically ill patients, yet few specific clinical and endoscopic features are known. In this study, we investigated the common clinical and endoscopic features of CMV colitis in critically ill patients. Methods From January 1, 2000 to February 28, 2014, patients with a histopathological diagnosis of CMV colitis were retrospectively reviewed. We reviewed and analyzed the clinical presentation, primary diseases, serum CMV antibody, treatment, mortality, and endoscopic features of these patients. Results Eighteen patients were diagnosed as having CMV colitis and 15 CMV colitis patients were included in this study. The mean age was 65.7 years (range 42–92 years). Bloody diarrhea and persistent diarrhea were the most common initial presentations of CMV, and sepsis was the most common comorbidity found. CMV-IgM was positive in three (17%) patients, and CMV-IgG was positive in 14 (93.3%) patients. All patients received ganciclovir and 11 patients clinically improved. Four (26.6%) patients died and two patients had colon perforation. According to the severity of the diseases, endoscopic presentation of CMV colitis ranged from colonic mucosa edema, loss of vasculature, subepithelial hemorrhage, and circular or geographic ulcers to perforation. Ten (66.7%) patients had multiple ulcers and five (33.3%) patients had a single ulcer. Eleven (73.3%) patients had colitis involving distal to splenic flexure, and four (26.6%) patients had colitis involving the whole colon. Conclusion Critically ill patients who present with bloody stool or persistent diarrhea should be considered for the diagnosis of CMV colitis. The endoscopic presentation of CMV colitis is highly variable. We suggest that the endoscopic manifestation of CMV colitis can be divided into three stages: nonulcerative inflammatory stage, simple ulcerative stage, and complicated ulcerative stage.

Background & Aims Many patients with pancreatic ductal adenocarcinoma (PDAC) develop recurrent or metastatic diseases after surgery, so it is important to identify those most likely to benefit from aggressive therapy. Disruption of tissue microarchitecture is an early step in pancreatic tumorigenesis and a parameter used in pathology grading of glandular tumors. We investigated whether changes in gene expression during pancreatic epithelial morphogenesis were associated with outcomes of patients with PDAC after surgery. Methods We generated architectures of human pancreatic duct epithelial cells in a 3-dimensional basement membrane matrix. We identified gene expression profiles of the cells during different stages of tubular morphogenesis (tubulogenesis) and of PANC-1 cells during spheroid formation. Differential expression of genes was confirmed by immunoblot analysis. We compared the gene expression profile associated with pancreatic epithelial tubulogenesis with that of PDAC samples from 27 patients, as well as with their outcomes after surgery. Results We identified a gene expression profile associated with tubulogenesis that resembled the profile of human pancreatic tissue with differentiated morphology and exocrine function. Patients with PDACs with this profile fared well after surgery. Based on this profile, we established a 6−28 gene tubulogenesis-specific signature that accurately determined the prognosis of independent cohorts of patients with PDAC (total n = 128; accuracy = 81.2%−95.0%). One gene, ASPM , was down-regulated during tubulogenesis but up-regulated in human PDAC cell lines and tumor samples; up-regulation correlated with patient outcomes (Cox regression P = .0028). Bioinformatic, genetic, biochemical, functional, and clinical correlative studies showed that ASPM promotes aggressiveness of PDAC by maintaining Wnt-β-catenin signaling and stem cell features of PDAC cells. Conclusions We identified a gene expression profile associated with pancreatic epithelial tubulogenesis and a tissue architecture−specific signature of PDAC cells that is associated with patient outcomes after surgery.

Chan et al. report that treatment of tumor-bearing mice with low-dose metronomic chemotherapy prevents stromal secretion of ELR+ chemokines and induction of tumor-initiating cells usually observed with administration of drugs at maximum tolerated dose., Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.

Very few reports are available from the literature related to Enterococcus hirae infection in humans, which is more frequently seen in animals and birds. We report two patients with E hirae bacteremia caused by acute pyelonephritis and acute cholangitis. The clinical courses have been smooth on use of sensitive antibiotic therapy. In both cases, the primary sources and portals of entry are clearly identified.

In the published version of this paper the author Shu-Pin Huang's surname was incorrectly given as Hwang instead of Huang. This has now been corrected in the HTML and PDF versions of the paper.

Metastasis is the major cause of cancer mortality in androgen-independent prostate cancer (PCA) and understanding it is crucial to improving the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here we report that a novel Wnt activator ASPM (Abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation through augmenting the Wnt-β-catenin signaling in PCA. Functional studies showed that downregulation of ASPM expression attenuated the proliferation and invasive of PCA cells and reduced the number of prostate CSCs and inhibited cancer stemness and tumorigenesis. Mechanistically, ASPM interacts with dishevelled-3 (Dvl-3) and inhibits its proteasome-dependent degradation, thereby increasing the protein stability of Dvl-3 and enabling the β-catenin transcriptional activity in PCA cells. The clinical significance of the above findings was credentialed by the profound up-regulation of ASPM in metastatic PCA and the strong correlation of cytoplasmic ASPM expression with poor metastasis-free survival of patients with resected PCA. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of cancer stemness in PCA, which has important clinical and therapeutic significance (supported by Ministry of Science and Technology grants MOST 104-2314-B-400-022 and MOST 105-2314-B-400-018 and National Health Research Institutes NHRIs grant CA-106-PP-09 to K.K.T). Citation Format: Kelvin K. Tsai, Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan. ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 538.

Whilst traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. Treatment resistance and metastasis have been attributed to expansion of cancer stem-like cells (CSCs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximal tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts that induces the expression and secretion of ELR-motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into CSCs and promote their invasive behaviors, leading to paradoxical tumor aggression following the therapy. By contrast, the same total accumulated dose administered as a low-dose-metronomic chemotherapy regimen largely prevented the therapy-induced stromal ELR+-chemokine paracrine signaling for CSCs, thereby substantially enhancing treatment response and extending survival of mice carrying desmoplastic cancers (Chan et al, J. Exp. Med. 2016). These studies illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. Note: This abstract was not presented at the meeting. Citation Format: Kelvin K. Tsai, Tze-Sian Chan, Chung-Chi Hsu, Vincent C. Pai, Shenq-Shyang Huang, Valerie M. Weaver. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2017-4763

Hepatocelluar carcinoma (HCC) is the most lethal cancer in the world. Most HCC over-express c-Myc, which plays a critical role in regulating cellular growth, differentiation and apoptosis in both normal and neoplastic cells. c-Myc is among the most frequently overexpressed genes in human cancers. Overexpression of c-Myc in hepatic cells leads to development of hepatocellular carcinoma. Here, we review the current progress in understanding physiologic function and regulation of c-Myc as well as its role in hepatic carcinogenesis and discuss the association of c-Myc activation in chronic hepatitis B infection and the upregulation of HIF-1/VEGF. We also explore the possibility of treating HCC by inhibiting c-Myc and examine the pros and cons of such an approach. Although this strategy is currently not available in clinics, with recent advances in better drug design, pharmacokinetics and pharmacogenetics, inhibition of c-Myc might become a novel therapy for HCC in the future.

A 76-year-old female patient complained of intermittent palpitation, shortness of breath, and orthopnea for 10 days. The patient was found to have cardiomegaly, left ventricular dilatation secondary to moderate regurgitation, with impaired ventricular dysfunction and persistent sinus tachycardia. The patient also had a nodular goiter with increased uptake on radionuclide scan on the right side of the thyroid gland, low serum thyroid-stimulating hor-mone, with normal triiodothyronine, and free thyroxine. Plummer's disease with ventricular dysfunction was diagnosed. We present this rare case and a review of the literature.