Abstract
BackgroundExtracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it is essential to understand how acidosis exerts its diverse effects. TDAG8 is a proton-sensing G-protein-coupled receptor that can be activated by extracellular acidosis.MethodsTDAG8 gene expression was analyzed by bioinformatic analyses and quantitative RT-PCR in human hematological malignancies. Retroviral transduction was used to restore TDAG8 expression in U937, Ramos and other blood cancer cells. Multiple in vitro and in vivo tumorigenesis and metastasis assays were employed to evaluate the effects of TDAG8 expression on blood cancer progression. Western blotting, immunohistochemistry and biochemical approaches were applied to elucidate the underlying mechanisms associated with the TDAG8 receptor pathway.ResultsTDAG8 expression is significantly reduced in human blood cancers in comparison to normal blood cells. Severe acidosis, pH 6.4, inhibited U937 cancer cell proliferation while mild acidosis, pH 6.9, stimulated its proliferation. However, restoring TDAG8 gene expression modulated the U937 cell response to mild extracellular acidosis and physiological pH by reducing cell proliferation. Tumor xenograft experiments further revealed that restoring TDAG8 expression in U937 and Ramos cancer cells reduced tumor growth. It was also shown U937 cells with restored TDAG8 expression attached less to Matrigel, migrated slower toward a chemoattractant, and metastasized less in severe combined immunodeficient mice. These effects correlated with a reduction in c-myc oncogene expression. The mechanistic investigation indicated that Gα13/Rho signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis.ConclusionsThis study provides data to support the concept that TDAG8 functions as a contextual tumor suppressor down-regulated in hematological malignancies and potentiation of the TDAG8 receptor pathway may be explored as a potential anti-tumorigenic approach in blood cancers.
Highlights
Extracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism
T cell death associated gene 8 (TDAG8) gene expression is reduced significantly in hematologic malignancies in comparison to normal immune cells and leukocyte‐rich tissue Oncomine bioinformatics analysis identified that TDAG8 gene expression was reduced in multiple forms of blood cancer, including acute myeloid leukemia (AML) (2.2 and 6.1-fold) [31, 32], chronic lymphocytic leukemia (CLL) (3.3, 1.7, 2.3, and 2.6-fold) (Table 1) [31, 33,34,35], T-cell acute lymphoblastic leukemia (TCALL) (3.1-fold), B-cell childhood acute lymphoblastic leukemia (BCCALL) (2.5-fold), B-cell acute lymphoblastic leukemia (BALL) (2.4-fold), pro B-cell acute lymphoblastic leukemia (PBALL) (1.3-fold), hairy cell leukemia (HCl) (1.9-fold), and T-cell prolymphocytic leukemia (TCPLL) (3.9-fold) (Table 1) [31, 33, 36]
TDAG8 gene expression is reduced in several lymphomas such as diffuse large B-cell lymphoma (DLBCL) (1.4- and 1.9-fold) [33, 34], follicular lymphoma (FL) (1.4- and 2.0-fold) [33, 34], pleural effusion lymphoma (PEL) (2.7-fold) [33], and Burkitt lymphoma (BL) (1.8-fold) [33] (Table 1)
Summary
Extracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Extracellular acidosis has pleiotropic effects on tumor growth and cancer progression [10,11,12,13,14]. Tumor acidosis can stimulate cell death, reduce cell proliferation, and induce chromosomal instability of normal somatic cells and cancer cells [13,14,15,16]. Tumor cells that become resistant to extracellular acidosis have been reported more malignant and invasive [17, 18]. Extracellular tumor acidosis augments cancer progression in a Darwinian manner worsening disease prognosis. It is imperative to understand how tumor cells sense and respond to acidic surroundings for adequate comprehension of cancer development
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