A 61-year-old man was admitted for evaluation of an abnormal chest abnormal with progressive swelling in both hands, clubbing of all fingers and toes, and polyarthroceles. He was given a diagnosis of pulmonary hypertrophic osteoarthropathy (PHO) associated with primary lung cancer, and underwent an upper left lobectomy. Histopathological analysis revealed stage IIB adenocarcinoma of the lung with K-ras mutation, but with no evidence of epidermal growth factor receptor (EGFR). Postoperatively, his symptoms rapidly improved, and the preoperatively observed high levels of serum vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) decreased to normal levels after just 1 month. VEGF and IL-6 caused by the genetic mutation of K-ras might play a role in the pathogenesis of PHO with lung cancer.

A 53-year-old man was referred to our hospital due to a mediastinal mass found during a medical checkup in July 2009. He had a past history of hyperparathyroidism, for which he underwent surgery in 1994, and also had a family history in that his sister had multiple endocrine neoplasia type 1 (MEN1). He was given a diagnosis of MEN I on genetic testing. Chest CT revealed a mediastinal mass 4 cm in maximum dimension, and an atypical carcinoid was diagnosed according to mediastinal biopsy findings. Bone metastasis was detected and he was given cisplatin and etoposide. The tumor decreased in size by 30%, and was evaluated as showing partial response. Although there are some cases of MEN-related thymoma treated by surgery, a case which successfully responded to chemotherapy alone is thought to be extremely rare.

Cancer cells undergo distinct responses including anaerobic metabolism and angiogenesis, to cope with their hypoxic environment. These responses are achieved at least partly by the action of transcriptional factors, which are called hypoxiainducible factors (HIFs). HIFs consist of a constitutively expressed subunit of HIF-1beta and an oxygen-regulated subunit of HIF-1alpha (or HIF-2alpha and HIF-3alpha). In hypoxia, an HIF-1alpha subunit becomes stable and regulates the expression of target genes. Clinical and experimental evidence suggest that altered gene expression induced by HIFs in response to the hypoxic microenvironment is a contributing factor to increasing metastatic efficiency. Diffusion-limited hypoxia, a consequence of tumor cells that are distant from the vascular supply, was the original concept behind hypoxia in tumors, and it was suggested that perfusion-limited hypoxia(acute or fluctuating hypoxia), due to fluctuations in blood flow, might play an important role in tumors. However, the effects of fluctuating hypoxia on gene expression induced by HIFs have yet to be addressed. In the present review, we focus on a number of genes that have been implicated in the metastatic process, and have been found to be hypoxia-responsive.

Cancer cells acquire metastatic phenotypes by accumulating genetic and epigenetic abnormalities. DNA methylation is involved in epigenetic regulation of gene transcription and frequently altered with carcinogenesis. Two modes of aberrant DNA methylation, promoter hypermethylation and global hypomethylation, play a role in cancer metastasis with different mechanisms. Here, we discuss how the aberrant DNA methylation contributes to acquisition of metastatic phenotypes in cancer and review the recent trials for molecular diagnosis of cancer metastasis using methylation markers.

Target tissue-specific delivery and transcription of foreign genes are desirable for safe and effective gene therapy. Two approaches for this purpose, "Targeted Delivery" and "Targeted Expression", have been mainly reported. Among "Targeted Expression" approaches, microRNA (miRNA)-mediated "post-transcriptional de-targeting" has been recently demonstrated, and much attention has been focused on this approach. MiRNAs are an approximately 22-nt length non-coding RNA, and bind to imperfectly complementary sequences in the 3'-untranslated region (UTR) of target mRNA, leading to suppression of gene expression via post-transcriptional regulation. First, in order to reduce the hepatic transduction by Ad vectors, complementary sequences of liver-specific miRNA, miR-122a, were inserted into the 3'-UTR of the transgene expression cassette. Intratumor injection of this Ad vector resulted in approximately 100-fold lower hepatic expression than that of the conventional Ad vector, without reducing gene expression in the tumor. Second, complementary sequences for miRNAs selectively down-regulated in tumor cells were inserted into the E1 gene expression cassette in oncolytic Ads, which exhibit tumor cell-specific replication and antitumor effects. Recent studies demonstrated that expression of several miRNAs is exclusively reduced in tumor cells. Oncolytic Ads containing the miRNA complementary sequences showed reduced replication in the normal cells, without altering the antitumor effects. MiRNA-regulated gene expression system mediates "post-transcriptional de-targeting", in which translation of transgene is suppressed in a tissue-specific manner; however, tissue-specific transgene expression can be achieved by taking tropism of gene delivery vehicles into consideration and reducing the transgene expression in untargeted organs via miRNA-regulated gene expression system.