Oncotarget

Research Papers:

Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models

Mimma Bianco, Anna Gasparri, Luca Generoso, Emma Assi, Barbara Colombo, Lydia Scarfò, Maria T.S. Bertilaccio, Cristina Scielzo, Pamela Ranghetti, Eleonora Dondossola, Maurilio Ponzoni, Federico Caligaris-Cappio, Paolo Ghia and Angelo Corti _

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Oncotarget. 2016; 7:41725-41736. https://doi.org/10.18632/oncotarget.9407

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Abstract

Mimma Bianco1, Anna Gasparri1, Luca Generoso1, Emma Assi1, Barbara Colombo1, Lydia Scarfò2,3,4, Maria T.S. Bertilaccio5, Cristina Scielzo5, Pamela Ranghetti5, Eleonora Dondossola1, Maurilio Ponzoni3, Federico Caligaris-Cappio3,4,5, Paolo Ghia2,3,4, Angelo Corti1,4

1Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy

2B Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy

3Clinical Lymphoma Unit, Department of Onco-Hematology, San Raffaele Hospital, Milan 20132, Italy

4San Raffaele Vita-Salute University, Milan 20132, Italy

5Lymphoid Malignancies Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy

Correspondence to:

Angelo Corti, email: corti.angelo@hsr.it

Keywords: chromogranin A, vasostatin-1, chronic lymphocytic leukemia, tumor cell trafficking, endothelial barrier function

Received: February 16, 2016     Accepted: April 26, 2016     Published: May 17, 2016

ABSTRACT

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA1-76), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA1-439 (0.3 μg, i.v., or 1.5 μg/mouse, i.p.) can reduce the BM/blood ratio of leukemic cells in Eμ-TCL1 mice, a transgenic model, and decrease BM, lung and kidney infiltration in Rag2−/−γc−/− mice engrafted with human MEC1 CLL cells, a xenograft model. This treatment also reduced the loss of body weight and improved animal motility. In vitro, CgA enhanced the endothelial barrier integrity and the trans-endothelial migration of MEC1 cells, with a bimodal dose-response curve. Vasostatin-1, but not a larger fragment consisting of N-terminal and central regions of CgA (CgA1-373), inhibited CLL progression in the xenograft model, suggesting that the C-terminal region is crucial for CgA activity and that the N-terminal domain contains a site that is activated by proteolytic cleavage. These findings suggest that circulating full-length CgA and its fragments may contribute to regulate leukemic cell trafficking and reduce tissue infiltration in CLL.


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