Parathyroid hormone-related protein (PTHrP) signaling plays important roles in regulating the differentiation of chondrocytes in endochondral bone development. PTHrP signaling functions as an inhibitory effect on chondrocyte hypertrophy which is a terminal stage of differentiation at a growth plate. Mutations of the PTH÷PTHrP receptor have been identified in Jansen metaphyseal chondrodysplasia, Blomstrand's lethal chondrodysplasia, and enchondromatosis. Furthermore, genetic manipulations of the PTHrP and its receptor genes in mice have demonstrated the critical roles of these proteins in regulating both the switch between proliferation and differentiation of chondrocytes.

In the mechanisms of carcinogenesis, it is becoming apparent that not only genetic abnormalities including DNA mutations, but also epigenetic abnormalities are heavily involved. Simultaneously, certain kinds of compounds indicated anti-tumor activity through their epigenetic effects. Typical drugs, which have the epigenetic effects, are histone deacetylase(HDAC) inhibitors. So far, two types of HDAC inhibitors, vorinostat and romidepsin, are approved by the Food Drug Administration for cutaneous T-cell lymphoma in the U. S. A. Not only these two compounds but also many HDAC inhibitors are under clinical trials in monotherapy and combination therapy. For a better outcome, it is very important to establish the appropriate biomarkers and appropriate combination based on mode-of-action for HDAC inhibitors, similar to other molecular-target antitumor drugs.

Amino acid alterations or insufficient protein synthesis caused by the mutation on genes has long been recognized as the main mechanism of silencing of suppressor genes leading to carcinogenesis. However, epigenetic silencing of the cancer related genes induced by hyper-methylation of promoter is recognized as an additional important molecular mechanism for carcinogenesis. Differing molecular mechanisms of colorectal carcinogenesis have become known after advanced understanding of genes silenced by promoter methylation.

Epigenetics mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in normal cells. Certain forms of histone methylation induce local heterochromatin formation, which is readily reversible, whereas DNA methylation leads to stable long-term repression. The precise epigenomic landscape present in normal cells undergoes extensive distortion in cancer. These characteristic epigenetic mechanisms are thought to be associated with tumor formation and progression. The reversible nature of epigenetic changes has led to the emergence of the field of epigenetic therapy, which may lead to potent and promising cancer treatment.

Epigenetic alterations such as DNA methylation and histone modification play a role in gene silencing in tumorigenesis. DNA methylation affects the expression of genes involved in cell cycle checkpoint, apoptosis, and DNA repair. Recently, epigenetic alterations are shown to play a role in silencing microRNA. Mutations of DNA methyltransferase and histone modification enzymes such as DNMT3A, UTX and EZH2 have been shown in various types of tumors. Genes involved in epigenetic regulation may be novel targets of cancer therapy in the near future.

We report herein a rare female case of bladder pheochromocytoma with familial clustering. Her mother had received an operation for bladder pheochromocytoma. When the present case was 20 years of age, body weight loss and fever appeared. Thereafter, nausea, vomiting and palpitation occurred especially at urination, and hypertension and tachycardia emerged. She was referred to our hospital for a further check up of hypertension at the age of 28 years. Her blood pressure was 176/130 mmHg, and pulse rate, 103/min. Hemorrhage and hard exudate were observed at the optic fundi. Twenty-four-hour ambulatory blood pressure monitoring disclosed that her hypertension was characterized by non-dipper type features and transient increases in both blood pressure and pulse rate occurring, especially at urination. Plasma noradrenalin level (14,399 pg/mL)was remarkably elevated, although the plasma adrenalin level (52 pg/mL) was within the normal limits. Computed tomography (CT) showed a mass lesion (7 cm in diameter) with central necrosis in the urinary bladder. 123I-MIBG showed strong uptake in the mass detected by CT. Venous blood sampling disclosed that the plasma noradrenalin concentration was highest at the lower level of the inferior vena cava. Therefore, a diagnosis of bladder pheochromocytoma with familial clustering was made and the pheochromocytoma was surgically removed.