ANGPTL4

People with diabetes who experience periods of low blood sugar -- a common occurrence in those new to blood sugar management -- are more likely to have worsening diabetic eye disease. Now, researchers say they have linked such low blood sugar levels with a molecular pathway that is turned on in oxygen-starved cells in the eye. People with diabetes who experience periods of low blood sugar -- a common occurrence in those new to blood sugar management -- are more likely to have worsening diabetic eye disease. Now, researchers at Johns Hopkins Medicine say they have linked such low blood sugar levels with a molecular pathway that is turned on in oxygen-starved cells in the eye. The research, involving human and mouse eye cells and intact retinas grown in a low sugar (low glucose) environment in the laboratory, as well as mice with low glucose levels, was published in the January issue of Cell Reports. "Temporary episodes of low glucose happen once or twice a day in people with insulin-dependent diabetes and often among people newly diagnosed with the condition," says Akrit Sodhi, M.D., Ph.D., the Branna and Irving Sisenwein Professor of Ophthalmology at the Wilmer Eye Institute at Johns Hopkins Medicine. Low glucose levels can also occur during sleep in people with non-insulin dependent diabetes. "Our results show that these periodic low glucose levels cause an increase in certain retinal cell proteins, resulting in an overgrowth of blood vessels and worsening diabetic eye disease," adds Sodhi. Eye disease among people with diabetes is among the most preventable causes of blindness in the U.S. Diabetic retinopathy, which occurs in up to a third of people with diabetes, is characterized by the overgrowth of abnormal blood vessels in the retina. Sodhi says the current study suggests that people with diabetic retinopathy may be particularly vulnerable to periods of low glucose, and keeping glucose levels stable should be an important part of glucose control. For the study, the researchers analyzed protein levels in human and mouse retinal cells and intact retinas grown in an environment of low glucose in the laboratory, as well as in mice that had occasional low blood sugar. The researchers found that low glucose levels in human and mouse retinal cells caused a cascade of molecular changes that can lead to blood vessel overgrowth. First, the researchers saw that low glucose caused a decrease in retinal cells' ability to break down glucose for energy. When the researchers looked specifically at so-called Müller glial cells, which are supportive cells for neurons in the retina and rely primarily on glucose for energy production, they found that the cells increased the expression of the GLUT1 gene, which makes a protein that transports glucose into cells. The researchers found that, in response to low glucose, the cells increased levels of a transcription factor, called hypoxia-inducible factor (HIF)-1α. This turned on the cellular machinery -- including GLUT1 -- needed to improve their ability to utilize available glucose, preserving the limited oxygen available for energy production by retinal neurons. However, in low-oxygen environments, as occurs in the retinas of patients with diabetic eye disease, this normal, physiologic response to low glucose triggered a flood of HIF-1α protein into the cells' nucleus, the cell's control center. This resulted in an increase in the production of proteins such as VEGF and ANGPTL4, which cause the growth of abnormal, leaky blood vessels -- the key culprit of vision loss in people with diabetic eye disease. The researchers plan to study whether low glucose levels in people with diabetes may impact similar molecular pathways in other organs, such as the kidney and brain. Sodhi says the HIF-1α pathway may serve as an effective target for developing new treatments for diabetic eye disease. Other researchers involved in the study include Chuanyu Guo, Monika Deshpande, Yueqi Niu, Isha Kachwala, Haley Megarity, Taylor Nuse, Savalan Babapoor-Farrokhran, Michael Ramada, Jaron Sanchez, Neelay Inamdar and Thomas V. Johnson of Johns Hopkins; Miguel Flores-Bellver and Maria Valeria Canto-Soler of the University of Colorado; and Silvia Montaner of the University of Maryland. Sodhi is a co-founder of and holds equity in HIF Therapeutics Inc. This arrangement has been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies. Funding for the research was provided by the National Institutes of Health's National Eye Institute (R01EY029750, R01EY025705, EY001765); Research to Prevent Blindness; the CellSight Development Fund; the Doni Solich Family Chair in Ocular Stem Cell Research; and the Branna and Irving Sisenwein Professorship in Ophthalmology.

The transport of molecules along the cell's skeleton plays a role in cancer metastasis, researchers show. Metastases occur when cancer cells leave a primary tumor and spread throughout the body. For this, they have to break connections with neighboring cells and migrate to other tissues. Both processes are promoted by signalling molecules released by the cancer cells, which thereby increase the malignancy of tumors. A research team led by Prof. Dr. Robert Grosse and Dr. Carsten Schwan from the University of Freiburg found that the release of these so-called prometastatic factors is influenced by the cells' skeleton. The study was published in Advanced Science. Actin has several functions in cancer propagation Actin filaments are part of the cell skeleton and essential for stability and motility. They form a network that dynamically builds up and gets broken down by the addition or detachment of building blocks at the filaments' ends. These processes are precisely regulated by other molecules, such as so-called formins. The dynamics of the actin-network enable the locomotion of cells, for example during development or wound closure, but also that of spreading cancer cells. Actin also plays a role in the transport of substances within the cell. However, this is less well understood than that of other intracellular transport mechanisms. The Freiburg researchers now found that the actin-network also enables the release of prometastatic factors. For their study, they used high-resolution microscopy to track the movement of individual transport vesicles within living cancer cells. "We observed that ANGPTL4-loaded vesicles are conveyed to the periphery of the cell by means of dynamic and localized polymerization of actin filaments," says Grosse, who is a member of the Cluster of Excellence CIBSS -- Centre for Integrative Biological Signalling Studies at the University of Freiburg. ANGPTL4 is an important prometastatic factor that promotes the formation of metastases in various types of cancer. FMNL2 controls the transport of ANGPTL4 along actin filaments Based on the microscopic observations and genetic analyses, the scientists conclude that the vesicles' movement is controlled by the formin-like molecule FMNL2 by initiating polymerization -- i.e. elongation -- of actin filaments directly at the vesicle. "We already knew that increased FMNL2 activity has prometastatic effects in many types of tumors," says Grosse. "In our current work we could now demonstrate an important underlying process and a connection to the TGFbeta signalling pathway." According to the scientist, this knowledge could be used for tumor diagnostics or therapy. for example, by developing an antibody that indicates the presence of active FMNL2 or pharmacologically targets active, phosphorylated FMNL2.

Why do metastases often only appear after the original tumor has been surgically removed? Scientists have now published an explanation for this phenomenon. They were able to identify a messenger substance of the cancer cells that locally promotes the growth of the primary tumor. In the blood, the messenger is split into two fragments, one of which suppresses metastasis. Tumor-bearing mice treated with the metastasis-inhibiting fragment survived cancer longer than untreated animals. Why do metastases often only appear after the original tumor has been surgically removed? Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Mannheim Medical Faculty of Heidelberg University have now published an explanation for this phenomenon. They were able to identify a messenger substance of the cancer cells that locally promotes the growth of the primary tumor. In the blood, the messenger is split into two fragments, one of which suppresses metastasis. Tumor-bearing mice treated with the metastasis-inhibiting fragment survived cancer longer than untreated animals. Cancer doctors are familiar with the observation: in many of their patients, the usually life-threatening metastases only appear after the original tumor has been surgically removed. This phenomenon is particularly common in breast cancer and black skin cancer. Physicians have derived the concept of "concomitant tumor resistance" from this observation. It states that the original cancer focus, also called the primary tumor, can suppress the growth of the daughter tumors known as metastases. The causes of this phenomenon are as yet poorly understood. Experts assume that the immune system plays a role, together with so-called angiogenic factors, which influence the connection of the metastases to the blood vessel system. From a size of about one millimeter, the daughter tumors depend on being supplied by blood vessels. Researchers were able to show several years ago that, depending on the tissue environment, tumors either release messenger substances that promote the formation of new blood vessels or factors that suppress the sprouting of new veins. Scientists led by Hellmut Augustin and Moritz Felcht of the German Cancer Research Center and the Mannheim Medical School of Heidelberg University have now taken a closer look at the messenger angiopoietin-like 4 (ANGPLT4). "We became aware of ANGPLT4 because there are many contradictory publications on this factor," Augustin said. "While ANGPLT4 was initially described as promoting the formation of new blood vessels and thus also promoting cancer, other studies were able to prove the exact opposite and show that ANGPLT4 inhibits the development of metastases." In comprehensive series of experiments on human and mouse tumors, the Heidelberg-Mannheim team elucidated a surprising mechanism. Among 38 different messenger substances that act on vascularization and possibly on concomitant tumor resistance, ANGPLT4 was found to be one of the molecules most strongly correlated with progressive tumor growth ANGPLT4 is produced by cells of the primary tumor and locally promotes its growth. However, if the messenger substance is released into the bloodstream, it is cleaved. The two cleavage products are called nANGPLT4 and cANGPLT4. For reasons not yet fully understood, the n fragment (nANGPLT4) is found almost exclusively in serum. nANGPLT4, however, binds to a different receptor than either the intact molecule or the c fragment. This receptor switch leads to the suppression of vessel growth and thus also the outgrowth of macrometastases. The researchers demonstrated this in numerous experimental approaches: Tumors transferred to mice formed fewer metastases after treatment with the n-fragment, and the animals survived longer. "Of course, surgical removal of the primary tumors remains the gold standard in the treatment of most cancers," says Moritz Fecht. "But we now understand that this simultaneously dries up the source of the metastasis-suppressing n fragment. If nANGPLT4 is missing, individual dormant metastatic tumor cells can become active and grow into a dangerous macrometastasis," says Moritz Felcht. "By cleaving the protein in the body and the resulting opposite functions in tumor metastasis, we can now explain the contradictory results of previous studies." "Many cancer patients could benefit from drugs that effectively suppress metastatic outgrowth. However, some of these agents have already failed in clinical trials. But in view of the enormous gain that such a drug could mean for those affected, it is worthwhile to continue researching ANGPLT4 preclinically and then clinically," Hellmut Augustin sums up. Corinne Hübers, Ashik Ahmed Abdul Pari, Denise Grieshober, Martin Petkov, Alexander Schmidt, Tatjana Messmer, Christian Moritz Heyer, Sebastian Scholch, Stephanie Kapel, Nicolas Gengenbacher, Mahak Singhal, Benjamin Schieb, Claudine Fricke, Rainer Will, Kim Remans, Jochen Sven Utikal, Christoph Reissfelder, Matthias Schlesner, Kairbaan M. Hodivala-Dilke, Sander Kersten, Sergij Goerdt, Hellmut G. Augustin and Moritz Felcht: Primary tumor-derived systemic nANGPTL4 inhibits metastasis. Journal of Experimental Medicine 2022, DOI: The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer. Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-pro of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients. The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers. 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