SECTM1 Produced by Tumor Cells Attracts Human Monocytes Via CD7-mediated Activation of the PI3K Pathways

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2013-11-13

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Abstract

Tumor-associated macrophages (TAMs) have essential roles in tumor progression and metastasis. Tumor cells recruit myeloid progenitors and monocytes to the tumor site, where they differentiate into TAMs; however, this process is not well studied in humans. Here we show that human CD7, a T-cell and NK cell receptor, is highly expressed by monocytes and macrophages. Expression of CD7 decreases in M-CSF-differentiated macrophages and in melanoma-conditioned medium-induced macrophages (MCMI/Mφ) in comparison to monocytes. A ligand for CD7, SECTM1 (secreted and transmembrane protein 1), is highly expressed in many tumors, including melanoma cells. We show that SECTM1 binds to CD7 and significantly increases monocyte migration by activation of the PI3K (phosphatidylinositol 3'-kinase) pathway. In human melanoma tissues, tumor-infiltrating macrophages expressing CD7 are present. These melanomas, with CD7-positive inflammatory cell infiltrations, frequently highly express SECTM1, including an N-terminal, soluble form, which can be detected in the sera of metastatic melanoma patients but not in normal sera. Taken together, our data demonstrate that CD7 is present on monocytes and tumor macrophages and that its ligand, SECTM1, is frequently expressed in corresponding melanoma tissues, possibly acting as a chemoattractant for monocytes to modulate the melanoma microenvironment.

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10.1038/jid.2013.437

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Kaufman, RE (2013). SECTM1 Produced by Tumor Cells Attracts Human Monocytes Via CD7-mediated Activation of the PI3K Pathways. J. Investigative Dermatology, 134(4). pp. 1108–1118. 10.1038/jid.2013.437 Retrieved from https://hdl.handle.net/10161/26515.

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Scholars@Duke

Kaufman

Russel E. Kaufman

Professor Emeritus of Medicine

The overall focus of this laboratory has been the study of the genetic regulation of normal and leukemic hematopoietic cells. Hematopoietic stem cells are produced during embryonic and fetal development and migrate to fetal liver, spleen, thymus, and bone marrow to populate those organs for the "definitive" stages of hematopoiesis.

We initially cloned the genes that compose the beta globin gene locus and also characterized other genomic elements that reside in and help control the expression of the locus, including the discovery of L1 repeats.  We later identified specific regulatory elements that when mutated change the expression of the locus, resulting in persistent expression of fetal globins into adulthood.  Our description of mutations in globin genes also explained an unusual form of thalassemia.
Our focus shifted to the identification and characterization of genes that control hematopoiesis, especially the human c-kit gene, normally expressed on erythroid progenitors. We identified important regulatory elements in the gene and how it interacted with other hematopoietic transcription factors. Later we identified the ets transcription factors as mediators of its signaling pathway and isolated a novel ets transcription factor, designated PE-2/ERF. Finally, we characterized the human GATA-1 and GATA-2 gene regulatory elements and demonstrated that signaling through the Kit signal transduction pathway has direct effects on these genes, showing that Kit signal transduction in setting up the erythroid developmental program.

This laboratory also has isolated the gene encoding the T cell specific gene CD7, expressed in T cell progenitors. During the characterization of the regulation of this gene, we identified a novel gene, SECTM1, that is closely linked physically and is the ligand for CD7. SECTM1 plays a role in regulating the immune response as well as other biological functions, and this is our current focus.
Key Words: Hematopoiesis, c-kit, ets, erythropoiesis, leukemia, gene regulation

for more information, see http:marini.biochem.duke.edu/Faculty/Kaufman.html


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