University of Maryland Biotechnology Institute

About: University of Maryland Biotechnology Institute is a based out in . It is known for research contribution in the topics: Gene & Population. The organization has 1565 authors who have published 2458 publications receiving 171434 citations. The organization is also known as: UMBI.

Autophagy in human tumors: cell survival or death?

Abstract: The development of tumors involves multiple genomic changes that result in abnormal neoplastic cells and necessary alterations in the surrounding support tissue. Similar to the dynamics of a developing tissue or organism, tumors can be viewed as amalgamations of multiple cell types of epithelial, stromal, angiogenic and connective tissue origin that are intricately linked by their interactions. Tumor growth involves two essential deviations from the normal state including the induction of proliferative stimuli, such as c-Myc and E2F, and simultaneous suppression of potentially compensatory cell death. It is well recognized that apoptosis is impaired in many cancers by mutations in genes such as p53, but it remains to be determined if nonapoptotic cell death mechanisms are also impaired in neoplastic cells. While compelling evidence indicates that aberrations in cell proliferation and death are the critical determinants of neoplastic growth, recent discoveries suggest that less studied mechanisms may contribute to tumor growth control. Autophagy is an evolutionarily conserved mechanism of protein and organelle degradation that has been observed in organisms that are as different as yeast and humans. Autophagy involves the sequestration of cytoplasmic structures into vacuoles that are transported to lysosomes for degradation. Recent studies of autophagy suggest that this mechanism of proteolysis may function in the regulation of cell survival and death. There are at least three ways in which autophagy might enhance cancer cell survival. Autophagy may serve to optimize nutrient utilization in rapidly growing cancer cells when faced with hypoxic or metabolic stress similar to the starvation response observed in normal cells. Alternatively, autophagy might aid in the degradation of organelles such as depolarized mitochondria that activate death pathways. Autophagy might also prevent cells from accumulating free radical-induced damage to lethal levels by removing organelles that are sources or targets of such damage. While the role of autophagy in cell survival during nutrient deprivation is well characterized, less is known about the possible role of this form of proteolysis in cell death even though autophagy occurs in dying cells of diverse organisms. Therefore, it is important to consider the possibility that autophagy may play an important role in some forms of programmed cell death. While autophagy might commence as an adaptive response that sacrifices mass for homeostasis and enhances survival, cell death may ensue if the process is carried beyond a threshold. Thus, autophagy may suppress tumor growth by causing cell death, limiting cell size, or otherwise maintaining a low mutation rate, and decreasing the likelihood of aberrant growth. We initiated a morphological survey for autophagic structures in several different primary human tumors because of the paucity of evidence for autophagy in cancer (Table 1). Tissues were obtained from surgical resection specimens, fixed in 3% glutaraldehyde, processed and sectioned, examined by light microscopy to verify the presence and preservation of viable neoplastic tissue, and analyzed by transmission electron microscopy. Autophagic structures were observed in neoplastic cells, and displayed the morphological features of double and multilamellate membrane-bound vacuoles enclosing cytoplasmic content and organelles (Figure 1). These autophagic vacuoles were typically in the vicinity of the nucleus and were frequently adjacent to swirls of endoplasmic reticulum devoid of ribosomes. The nuclei of these cells lacked apoptotic features such as fragmentation and chromatin margination. Of the 12 tumors studied, seven had evidence of autophagy including ganglioneuroma, infiltrating ductal carcinoma of the breast, adenocarcinoma of the lung, pancreatic adenocarcinoma and pancreatic islet cell tumor. Taking into account the small sample size for some of the tumor types examined, it seems reasonable to expect that autophagy occurs in many tumors. The precise role of autophagy in cancer development, progression and response to therapy is not understood. The recognition of Beclin-1 (Atg6), a gene that functions in autophagy, as a haploinsufficient tumor suppressor raises intriguing possibilities about the importance of autophagy in cancer. It is possible that the mechanism of tumor suppression is through promotion of cell death. Autophagy peaks at precancerous stages and diminishes at the malignant stage in some rat tumor models, suggesting a tumor suppressor role. It is interesting that autophagy is regulated by some of the same pathways of cell growth control that are altered in tumor formation such as the PI3K system.

Early development of forebrain gonadotrophin-releasing hormone (GnRH) neurones and the role of GnRH as an autocrine migration factor.

Abstract: Normal migration of the gonadotrophin-releasing hormone (GnRH) neurones during early development, from the olfactory region to the hypothalamus, is crucial for reproductive development in all vertebrates. The establishment of the GnRH system includes tangential migration of GnRH perikarya as well as extension of GnRH fibres to various areas of the central nervous system (CNS). The exact spatio-temporal nature of this process, as well as the factors governing it, are not fully understood. We studied the development of the GnRH system and the effects of GnRH knockdown using a newly developed GnRH3:EGFP transgenic zebrafish line. We found that enhanced green fluorescent protein is specifically and robustly expressed in GnRH3 neurones and fibres. GnRH3 fibres in zebrafish began to extend as early as 26 h post-fertilisation and by 4-5 days post-fertilisation had developed into an extensive network reaching the optic tract, telencephalon, hypothalamus, midbrain tegmentum and hindbrain. GnRH3 fibres also innervated the retina and projected into the trunk via the spinal cord. GnRH3 perikarya were observed migrating along their own fibres from the olfactory region to the preoptic area (POA) via the terminal nerve ganglion and the ventral telencephalon. GnRH3 cells were also observed in the trigeminal ganglion. The establishment of the GnRH3 fibre network was disrupted by morpholino-modified antisense oligonucleotides directed against GnRH3 causing abnormal fibre development and pathfinding, as well as anomalous GnRH3 perikarya localisation. These findings support the hypothesis that GnRH3 neurones migrate from the olfactory region to the POA and caudal hypothalamus. Novel data regarding the early development of the GnRH3 fibre network in the CNS and beyond are described. Moreover we show, in vivo, that GnRH3 is an important factor regulating GnRH3 fibre pathfinding and neurone localisation in an autocrine fashion.