DF/HCC Program Affiliation

Member, Leukemia Program
Member, Cancer Immunology Program

Research Abstract

Mast cells release a diverse array of biologically active molecules (including cytokines, chemokines, leukotrienes, prostaglandins, amines, proteoglycans, and proteases) when these cells are activated through one of their surface receptors. Thus, these cells play a key role in inflammation. While it is well known that most allergic reactions are mast cell-dependent, the presence of increased numbers of mast cells in nearly all tumors suggests that these effector cells of the immune response also play prominent roles in cancer. Mast cells are a heterogeneous family of hematopoietic cells whose phenotype is dependent on the tissue microenvironment the mature cell eventually resides. In vitro and molecular biology approaches have been developed in this laboratory to identify the factors that regulate the differentiation and phenotypic properties of mouse and human mast cells. For example, by varying the culture conditions, bone marrow progenitor cells have been induced to differentiate and mature into populations of mast cells which differ in what mediators they express. A number of novel human and mouse mast cell-specific genes have been identified, and the transcripts are regulated as the mast cell's microenvironment is altered. For example, we identified a new cation-dependent, MC-restricted guanine exchange factor/phorbol ester receptor (designated as RasGRP4) that regulates MC development. This signaling protein controls what proteases and eicosanoids MCs eventually express. RasGRP1 is the first member of this family of signaling proteins, and dysregulation of RasGRP1 is the ninth leading cause virus-induced leukemia in mice. Preliminary data have suggested a role for RasGRP4 in mast cell leukemia and clear cell tumors of the kidney. The cis-acting elements and trans-acting DNA-binding proteins that regulate transcription of mast cell-specific genes are being identified, as well as the RNA-binding proteins that regulate the stability of their transcripts. At the genome level, how specific families of mast cell-specific protease genes are organized on chromosomes 14 and 17 are being investigated. Transgenic mice have been created that differ substantially in the number and phenotype of the mast cells that they have in their tissues. A novel adoptive transfer approach also has been developed to address the varied aspects of mast cell development and function in vivo. Lastly, what happens to a cancerous cell when it physcially interacts with a mast cell is being investigated.

Publications

• Thakurdas SM, Melicoff E, Sansores-Garcia L, Moreira DC, Petrova Y, Stevens RL, Adachi R. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J Biol Chem 2007 Apr 23;
  PMID: 17456473
• Habuchi H, Nagai N, Sugaya N, Atsumi F, Stevens RL, Kimata K. Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality. J Biol Chem 2007 May 25; 282(21):15578-88
  PMID: 17405882
• Abonia JP, Friend DS, Austen WG, Moore FD, Carroll MC, Chan R, Afnan J, Humbles A, Gerard C, Knight P, Kanaoka Y, Yasuda S, Morokawa N, Austen KF, Stevens RL, Gurish MF. Mast cell protease 5 mediates ischemia-reperfusion injury of mouse skeletal muscle. J Immunol 2005 Jun 1; 174(11):7285-91
  PMID: 15905575
• Yasuda S, Morokawa N, Wong GW, Rossi A, Madhusudhan MS, Sali A, Askew YS, Adachi R, Silverman GA, Krilis SA, Stevens RL. Urokinase-type plasminogen activator is a preferred substrate of the human epithelium serine protease tryptase epsilon/PRSS22. Blood 2005 May 15; 105(10):3893-901
  PMID: 15701722
• Wong GW, Yasuda S, Morokawa N, Li L, Stevens RL. Mouse chromosome 17A3.3 contains 13 genes that encode functional tryptic-like serine proteases with distinct tissue and cell expression patterns. J Biol Chem 2004 Jan 23; 279(4):2438-52
  PMID: 14583634
• Walsh JC, DeKoter RP, Lee HJ, Smith ED, Lancki DW, Gurish MF, Friend DS, Stevens RL, Anastasi J, Singh H. Cooperative and antagonistic interplay between PU.1 and GATA-2 in the specification of myeloid cell fates. Immunity 2002 Nov; 17(5):665-76
  PMID: 12433372
• Yang Y, Li L, Wong GW, Krilis SA, Madhusudhan MS, Sali A, Stevens RL. RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demon J Biol Chem 2002 Jul 12; 277(28):25756-74
  PMID: 11956218
• Humphries DE, Wong GW, Friend DS, Gurish MF, Qiu WT, Huang C, Sharpe AH, Stevens RL. Heparin is essential for the storage of specific granule proteases in mast cells. Nature 1999 Aug 19; 400(6746):769-72
  PMID: 10466726