Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth : Involvement of protein kinase C-θ activation

Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-θ (PKC-θ) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling. Inhibition of PKC-θ activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells. PKC-θ kinase MAP4K3, which plays a pivotal role in PKC-θ activation, also affected growth signaling in the presence of EP2/EP4 antagonists. Administration of EP2 and EP4 antagonists significantly inhibited the growth of an orthotopic xenograft of IGF-1-secreting pancreatic cancer cells, with increased phospho-PKC-θ and decreased phospho-ERK. Clinico-pathological analyses showed that 17.4% of surgical pancreatic cancer specimens were quadruple-positive for IGF-1R, EP2 (or EP4), MAP4K3, and PKC-θ. These results indicate a novel signaling crosstalk between EP2/EP4 and IGF-1R in cancer cells, and suggest that the MAP4K3-PKC-θ axis is central and could be exploited as a molecular target for cancer therapy

Subtype and targeted therapy for TNBC

Triple-negative breast cancer (TNBC) is a heterogenous disease. For personalized medicine, it is essential to identify and classify tumor subtypes to develop effective therapeutic strategies. Although gene expression profiling has identified several TNBC subtypes, classification of these tumors remains complex. Most TNBCs exhibit an aggressive phenotype, but some rare types have a favorable clinical course. In this review, we summarize the classification and characteristics related to the various TNBC subtypes, including the rare types. Therapeutic methods that are suitable for each subtype are also discussed. Of the intrinsic breast cancer subtypes identified by gene expression analysis, the basal-like subtype specifically displayed decreased expression of an estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) cluster. We also present results that characterize the TNBC and basal-like phenotypes. TNBC may be categorized into four major classes : basal-like, immune-enriched, mesenchymal, and luminal androgen receptor. Therapeutic strategies for each subtype have been proposed along with newly approved targeted therapies for TNBC, such as immune checkpoint inhibitors. Understanding the classification of TNBC based on gene expression profiling in association with clinicopathological factors will facilitate accurate pathological diagnosis and effective treatment selection

SCC INVADING CEREBRAL BLOOD VESSELS

Squamous cell carcinoma (SCC) is known to have less brain metastasis, but the reasons are not well established. Herein, we report the case of an 82-year-old man with recurrent cerebral hemorrhage of unknown cause ; upon brain biopsy, SCC was diagnosed infiltrating peripheral blood vessels of the brain and that it was state of micro-metastasis. It is possible that the blood-brain barrier blocked the infiltration of SCC into the brain parenchyma, and it did not form a mass in the brain parenchyma. In addition, because it did not form a mass, it could not be diagnosed as a metastatic brain tumor by contrast-enhanced magnetic resonance imaging or contrast-enhanced computed tomography. Among cases of recurrent cerebral hemorrhage of unknown cause in a short period, there may be cases of vascular infiltration without crossing the blood-brain barrier. Thus, if similar cases of recurrent cerebral hemorrhage of unknown cause is observed, it is necessary to distinguish metastatic brain tumors even if there is no evidence of suspected tumor on contrast-enhanced magnetic resonance imaging scan

Imaging features of a myoepithelial carcinoma of the nasal cavity : A case report and literature review

Myoepithelial carcinoma of the nasal cavity is extremely rare. We report the case of a 66-year-old man with myoepithelial carcinoma of the nasal cavity. Computed tomography (CT) and magnetic resonance imaging revealed a lobulated soft tissue mass with central necrosis and hemorrhage, as well as an invasion of the skull base and left orbit. The patient presented with continuous nasal congestion and heavy head and had no elevated level of squamous cell carcinoma-related antigen. CT, magnetic resonance imaging, or 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT revealed no evidence of a metastatic lesion. 18F-FDG accumulation in the tumor was inhomogeneous and moderate. Histopathological examination of the resected specimen confirmed a well-circumscribed solid tumor with septa, a small area of hemorrhage, and necrosis. The subsequent diagnosis was a myoepithelial carcinoma of the left nasal cavity. This case shows that nasal myoepithelial carcinoma might appear as a well-defined lobulated mass with hemorrhagic necrosis and intense contrast enhancement in the solid component. We conjecture that hemorrhagic necrosis and intense enhancement values may be potential markers of nasal myoepithelial carcinoma

Adipose tissue : Critical contributor to the development of prostate cancer

The prostate is surrounded by periprostatic adipose tissue. Although adipose tissue was thought to play limited physiological roles, it has recently been recognized as an active endocrine organ, secreting growth factors and adipokines. Epidemiologically, obesity is associated with prostate cancer progression. A major mechanism to explain the link between obesity and cancer includes the insulin and insulin-like growth factor (IGF)-1 axis, sex steroids, and adipokines. When prostate cancer cells invade periprostatic adipose tissue, adipose tissue contributes to create the tumor microenvironment, mainly via adipokine secretion. Furthermore, direct crosstalk between adipocytes and cancer cells can exist.We showed that fatty acid-binding protein 4 (FABP4) released from adipocytes was taken up into prostate cancer cells and may act as a carrier of an energy source for the invasion. Bone is an adipocyte-rich organ and is the common metastatic site of prostate cancer. In the microenvironment of bone metastases, tumor cells, osteoblasts, osteoclasts, adipocytes, and other stromal cells are interacting with one another and organizing a complex system. Thus, growing evidence implicates adipose tissue as a critical contributor to the development of prostate cancer. A deeper understanding of the mechanisms leads to more effective therapeutic strategies for prostate cancer

MONITORING ANAPLASTIC THYROID CANCER MODELS BY PET/CT

Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid carcinoma with a poor prognosis. Thus, suitable preclinical tumor models are required for the development of new ATC therapies. In the present study, orthotopic tumor xenograft models were established using ATC cell lines and SCID mice, and tumor invasion and the effects of anticancer drugs were evaluated using positron emission tomography/computed tomography (PET/CT) to repeatedly and non-invasively monitor these models. Three ATC cell lines (8305c, 8505c, and ACT-1) were used. Their sensitivities to two anticancer drugs (paclitaxel and lenvatinib) were investigated. The 8505c cell line was orthotopically implanted into SCID mice, which were then divided into three groups: no chemotherapy, paclitaxel (5 mg/kg, administered intraperitoneally, every week), and lenvatinib (5 mg/kg, oral route, every day) groups. PET/CT was performed and tumor growth and the effects of anticancer drugs based on tumor volume and fludeoxyglucose (FDG) uptake were evaluated. 8505c cells exhibited the highest sensitivity to the anticancer drugs. In mice implanted with 8505c cells, continuous increases in FDG uptake associated with tumor growth were detected on PET/CT in the group that received no chemotherapy. The tumor volume and FDG uptake increased by 91.5- and 2.4-fold, respectively, within 2 weeks. The increase observed in tumor volume was 26.9- and 12.2-fold in the paclitaxel and lenvatinib groups, respectively, within 2 weeks. Furthermore, the increase in FDG uptake was 1.8-fold and 1.6-fold in the paclitaxel and lenvatinib groups, respectively, within 2 weeks. In our orthotopic SCID mouse model, tumor growth and the effects of anticancer drugs were repeatedly and non-invasively monitored using PET/CT. The present method is useful for the development of new ATC treatments

W-derived BAC probes as a new tool for identification of the W chromosome and its aberrations in Bombyx mori

We isolated four W chromosome-derived bacterial artificial chromosome (W-BAC) clones from Bombyx mori BAC libraries by the polymerase chain reaction and used them as probes for fluorescence in situ hybridization (FISH) on chromosome preparations from B. mori females. All four W-BAC probes surprisingly highlighted the whole wild-type W sex chromosome and also identified the entire original W-chromosomal region in W chromosome-autosome translocation mutants. This is the first successful identification of a single chromosome by means of BAC-FISH in species with holokinetic chromosomes. Genomic in situ hybridization (GISH) by using female-derived genomic probes highlighted the W chromosome in a similar chromosome-painting manner. Besides the W, hybridization signals of W-BAC probes also occurred in telomeric and/or subtelomeric regions of the autosomes. These signals coincided well with those of female genomic probes except one additional GISH signal that was observed in a large heterochromatin block of one autosome pair. Our results support the opinion that the B. mori W chromosome accumulated transposable elements and other repetitive sequences that also occur, but scattered, elsewhere in the respective genome. Edited by: E.R. Schmid

Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats

The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson’s disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O6-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats