The Roles of Dietary PPARγ Ligands for Metastasis in Colorectal Cancer

Dietary peroxisome proliferator-activated receptor (PPAR)γ ligands, linoleic acid (LA) and conjugated linoleic acid (CLA), showed anticancer effects in colorectal carcinoma cells. LA is metabolized by two pathways. Cyclooxygenase (COX)-2 produces procarcinogenic prostaglandin E2, whereas 15-lipoxygenase (LOX)-1 produces PPARγ ligands. The 15LOX-1 pathway, which is dominant in colorectal adenomas, was downregulated and inversely COX-2 was upregulated in colorectal cancer. LA and CLA inhibited peritoneal metastasis of colorectal cancer cells in nude mice. The inhibitory effect was abrogated by PPARγ antisense treatment. A continuous LA treatment provided cancer cells quiescence. These quiescent cells formed dormant nests in nude mice administrated LA. The quiescent and dormant cells showed downregulated PPARγ and upregulated nucleostemin. Thus, short-term exposure to dietary PPARγ ligands inhibits cancer metastasis, whereas consistent exposure to LA provides quiescent/dormant status with possible induction of cancer stem and/or progenitor phenotype. The complicated roles of dietary PPARγ ligands are needed to examine further

MULTIPLE ROLES OF HMGB1 IN CANCER CELLS

HMGB1 is a non-histone chromosomal protein, a secretory protein binding to the receptor for advanced glycation end products in cancer cells and monocyte-lineage immune cells. HMGB1 enhances proliferation, motility, invasion, and survival of cancer cells. HMGB1 associated with DNA repair of anti-cancer drug-induced DNA damage. Importantly, HMGB1 is released from necrotic cancer cells and induces re-growth of the remnant cancer cells. In contrast, HMGB1 induces apoptosis in monocyte-lineage immune cells and inhibits tumor-infiltrating macrophages and dendritic cells, lymph node sinus macrophages, liver Kupffer cells to attenuate anti-cancer immune responses and anti-metastatic organ defense

MOLECULAR MARKERS OF PERITONEAL DISSEMINATION IN GASTRIC CANCER

Peritoneal dissemination is a special condition of gastric cancer metastasis, which worsens the quality of patients' lives and is often difficult to control. In this study, we describe the basic features of the peritoneal dissemination of gastric cancer. Some molecular events are associated with the peritoneal dissemination, including c-met gene amplification, chromosome 7q deletion, and Reg Ⅳ overexpression. Especially, Reg Ⅳ overexpression enhances the antiapoptotic property of gastric cancer cells. In contrast, activation of PPARg inhibits the peritoneal dissemination by the pro-apoptotic effect

Significance of Trans Fatty Acids in Cancer.

Trans fatty acids (TFAs) are a recent focus of health problems. TFA is a definitive risk factor for cardiovascular diseases and the death. TFA is also possible risk factor for Alzheimer's disease, obesity, diabetes, fatty liver, and ovulation infertility. The relationship between TFA and carcinogenic risk is controversial; however, TFA is reported to increase the risk of breast cancer and prostate cancer. Elaidic acid (EA), a trans form of oleic acid, enhances cancer cell growth, invasion, and anti-apoptotic survival. In animal models, EA promotes tumor growth and metastasis to the lung, liver, and peritoneum. EA induces sternness in cancer cells through transactivation of EFGR via SRC from GPR40/120 as receptors in EA-integrated cholesterol rafts. Activated EGFR relays the signals to activate canonical and non-canonical wnt pathways and to inactivate notchl pathways. EA also increases miR-494, which inhibits cell differentiation through decrease of target genes. Continuous EA feeding with dosage alteration increased cancer cell sternness. EA diminishes the efficiency of 5-fluorouracil by increasing residual cancer stem cells. These findings suggest that TFA is a relevant cancer promoting factor. The decision to remove TFA from foods made by the FDA might have an impact on cancer clinics

SIGNIFICANCE OF ANGIOTENSIN SYSTEM IN PROGRESSION OF COLORECTAL CANCER

Colorectal cancer (CRC) cells possess an angiotensin activation mechanism provided by the expression of renin and chymase. Renin expression is induced by hyperglycemic condition. Since angiotensinogen is produced in the liver, CRC cells with angiotensin-activating machinery possess an advantage to metastasize to the liver. In human CRC cases, the diabetes complicated patients show higher concentrations of renin, angiotensin-Ⅱ in the primary tumors, and more progressed disease stage, especially, liver metastasis in an association with HbA1c levels than those in the patients without diabetes. Concurrent treatment with anti-angiotensin and hypoglycemic agents shows a synergic effect of decrease of liver metastasis and improvement of the survival of diabetic mice of CRC liver metastasis model. The effect of anti-angiotensin treatment and blood sugar control as a baseline management of the colon cancer patients with the diabetic condition is needed to be examined in clinical situation for prevention of liver metastasis

A Novel Strategy of Dual Inhibition of Distinct Metabolic Features in Osteosarcoma

Mitochondria are the places for the energy production of the cells, while reactive oxygen species (ROS) are also produced alongside. In recent years, it has been reported that cancer stem cells metabolize predominantly through oxidative phosphorylation (OXPHOS) rather than glycolysis. Targeting OXPHOS achieved by suppression of ATP synthesis through mitochondrial ATP synthase could be a potential therapeutic option against cancer stem cells. Since c-Myc inhibition is considered to lead a metabolic flux to OXPHOS from glycolysis, the combinatory inhibition of both OXPHOS and glycolysis could be a strong candidate for the treatment of malignant tumors. In this chapter, we will discuss about the mitochondria metabolism as the potential therapeutic target in osteosarcoma stem cells, and the synergistic effects of combination of OXPHOS inhibitor with c-Myc inhibitor, which target both OXPHOS-dominant cancer stem cells and glycolysis-dominant non-cancer stem cells, will be discussed

AKT Plays a Crucial Role in Gastric Cancer.

The AKT protein is involved in the phosphatidylinositol-3 kinase signaling pathway and is a vital regulator of survival. proliferation, and differentiation of various types of cells. Helicobacter pylori induce epithelial cell proliferation and oxidative stress in chronic gastritis. These alterations lead to telomere shortening and resultant telomerase activation. Specifically, AKT is activated by H. pylori-induced inflammation; it subsequently promotes expression of human telomerase reverse transcriptase, which encodes a catalytic subunit of telomerase; and induces telomerase activity, which is an essential process of carcinogenesis. AKT activation is increased in gastric mucosa with carcinogenic properties and is associated with low survival of patients with gastric cancer. These findings suggest that AKT is pivotal in gastric carcinogenesis and progression

Relationships between the magnitude of representational momentum and the spatial and temporal anticipatory judgments of opponent’s kicks in taekwondo

For successful actions in a fast, dynamic environment such as sports, a quick successful anticipation of a forthcoming environmental state is essential. However, the perceptual mechanisms involved in successful anticipation are not fully understood. This study examined the relationships between the magnitude of representational momentum (RM) as a forward displacement of the memory representation of the final position of a moving object (which implies that observers perceptually “see” a near future forthcoming dynamic environmental state) and the temporal and spatial anticipatory judgments of the opponent’s high or middle kicks in taekwondo. Twenty-seven participants (university taekwondo club members and non-members) observed video clips of taekwondo kicks that vanished at one of 10 frame positions prior to the kick impact and performed three tasks consecutively: anticipatory coincidence timing (CT) with the arrival of kick impact, judgment of the kick type (high and middle kicks) by forced choice, and judgment of the vanishing frame position (measuring RM). Our results showed significant group effects for the number of correct kick-type judgments and the judgment threshold for kick-type choice (kick-typeJT), which was estimated in terms of individual psychometric function curves. A significant correlation was found between the magnitude of RM (estimated at kick-typeJT) and kick-typeJT, but not between the CT errors (estimated at kick-typeJT) and kick-typeJT. This indicates that the magnitude of RM may play an influential role in quick kick-type judgments, but not in coincidence timing while observing an opponent’s kick motion. These findings suggest that subjective anticipatory perception or judgment of the future spatial state is vital to anticipatory actions under severe time constraints

Protumoral Effect of Angiotensin System.

Colorectal cancer (CRC) cells possess an angiotensin activation mechanism provided by the expression of renin and chymase. Renin expression is induced by a hyperglycemic condition. Since angiotensinogen is produced in the liver, CRC cells with angiotensin-activating machinery possess an advantage to metastasize to the liver. In human CRC cases, the diabetes-complicated patients show higher concentrations of renin and angiotensin-Ⅱ in the primary tumors, and a more progressed disease stage, especially, liver metastasis in association with HbA1c levels than those in the patients without diabetes. Concurrent treatment with anti-angiotensin and hypoglycemic agents shows a synergic effect of decreasing liver metastasis and improving the survival of diabetic mice in the CRC liver metastasis model. MAS1-angiotensin1-7 is a negative regulator of the AGTR1-angiotensin Ⅱ axis in breast cancer. Notably, MAS1 is overexpressed in triple negative breast cancer, which might be a novel molecular target for the treatment-refractory entity of breast cancer. Nuclear AGTR2 and intracellular angiotensin-Ⅱ play a role in anti-apoptotic and anti-oxidative stress properties. These functions of nuclear AGTR2 might mitigate "anti-tumoral side effects" of AGTR1 and angiotensin-Ⅱ system, which enhance mainly tumor progression. The effect of anti-angiotensin treatment such as ARB and blood sugar control as ab aseline management of many cancer patients needs to be examined in a clinical situation for prevention of RAS-induced tumor progression

S-1投与ラットにおける味覚障害の想定される末梢メカニズム

BACKGROUND: Taste disorders are frequently observed in cancer patients undergoing chemotherapy and are serious adverse events which impair the quality of life (QoL) of the cancer patient. Nevertheless, taste disorder mechanisms in cancer patients undergoing chemotherapy have not yet been fully elucidated. The aim of this study was to reveal taste disorder-related peripheral mechanisms using the two-bottle preference test (TBPT) and histological examination of tongues by hematoxylin-eosin staining and immunohistochemistry with protein-gene product 9.5. METHODS: In the TBPT, one bottle was filled with the 0.01 mM quinine hydrochloride (quinine), as a bitter compound, and the other was filled with water. Doses of 50 and 100 mg kg-1 day-1 S-1 (tegafur/gimeracil/oteracil potassium) are lethal to Wistar rats. Therefore, doses ranging from 2-20 mg kg-1 day-1 were administered to the rats for 3 weeks. The S-1 dose of 2 mg kg-1 day-1 corresponds to the clinical dose administered to cancer patients. The part of the tongue containing the circumvallate papillae was excised the following TBPT. RESULTS: The rate of increase in terms of the average preference rate for the quinine vs. all intake (quinine plus water) was significant from the initial S-1 period to the final one, compared with that in control rats, suggesting the possibility of a worsening sensation for the bitter taste. In S-1 rats, the area of taste nerve fibers were significantly decreased and the rate of degeneration of intra-tongue ganglionic nerve cells was significantly increased. These changes were significantly correlated with the rate of increase in average preference rate of the quinine. CONCLUSION: Neuropathy of the gustatory nerve at the periphery may be involved in taste disorders induced by an anticancer drug.博士（医学）・乙1329号・平成26年3月17