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Regulation of Tumor Growth by Circulating Full-Length Chromogranin A www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 45 Research Paper Regulation of tumor growth by circulating full-length chromogranin A Flavio Curnis1,*, Alice Dallatomasina1,*, Mimma Bianco1,*, Anna Gasparri1, Angelina Sacchi1, Barbara Colombo1, Martina Fiocchi1, Laura Perani2, Massimo Venturini2, Carlo Tacchetti2, Suvajit Sen3, Ricardo Borges4, Eleonora Dondossola1, Antonio Esposito2,5, Sushil K. Mahata6 and Angelo Corti1,5 1 Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy 2 Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy 3 University of California, Los Angeles, CA, USA 4 La Laguna University, Tenerife, Spain 5 Vita-Salute San Raffaele University, Milan, Italy 6 VA San Diego Healthcare System and University of California, San Diego, La Jolla, CA, USA * These authors have contributed equally to this work Correspondence to: Flavio Curnis, email: [email protected] Correspondence to: Angelo Corti, email: [email protected] Keywords: chromogranin A, angiogenesis, tumor perfusion, endothelial cells, protease-nexin-1 Received: September 9, 2016 Accepted: September 17, 2016 Published: September 24, 2016 ABSTRACT Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves. Tumor growth inhibition was associated with reduction of microvessel density and blood flow in neoplastic tissues. Neutralization of endogenous CgA with antibodies against its C-terminal region (residues 410-439) promoted tumor growth. Structure-function studies showed that the C-terminal region of CgA contains a bioactive site and that cleavage of this region causes a marked loss of anti-angiogenic and anti-tumor potency. Mechanistic studies showed that full-length CgA could induce, with a U-shaped dose-response curve, the production of protease nexin-1 in endothelial cells, a serine protease inhibitor endowed of anti-angiogenic activity. Gene silencing or neutralization of protease nexin-1 with specific antibodies abolished both anti-angiogenic and anti-tumor effects of CgA. These results suggest that circulating full-length CgA is an important inhibitor of angiogenesis and tumor growth, and that cleavage of its C-terminal region markedly reduces its activity. Pathophysiological changes in CgA blood levels and/or its fragmentation might regulate disease progression in cancer patients. INTRODUCTION cardiomyocytes and, in certain conditions, by keratinocyte [1, 3-5]. An increasing number of studies have shown that Human chromogranin A (CgA) is a 439 residue- CgA and certain CgA-derived peptides, called vasostatin-1, long protein stored in the dense-core granules of many pancreastatin, catestatin and serpinin, can regulate the neuroendocrine cells and neurons, and exocytotically cardiovascular system and metabolism, suggesting released into the blood to reach about 0.5 nM levels [1, 2]. that this protein can exert extra-cellular functions [1]. CgA is also expressed in lower amounts by granulocytes, Increased levels of CgA have been immunologically www.impactjournals.com/oncotarget 72716 Oncotarget detected in the blood of patients with neuroendocrine fibrosarcomas, Lewis lung carcinoma and mammary tumors or with tumors that undergo neuroendocrine adenocarcinomas, as well as orthotopic subcutaneous and differentiation, including prostate, breast and non-small metastatic (lung) melanomas. cell lung cancer [2, 6-8]. For these reasons CgA is widely We show that full-length CgA, but not fragments used as a serological marker for neuroendocrine tumor lacking the C-terminal region, can inhibit tumor growth in diagnosis or for monitoring tumor progression/regression all these models, with U-shaped dose-response curves, and after therapy. However, patients with non-neuroendocrine we provide evidence that an active site is located in the tumors may also have abnormal levels of circulating CgA. C-terminal region. Furthermore, we show that full-length For example, increased levels of immunoreactive CgA CgA can impair angiogenesis, tumor perfusion and tumor have been observed in a subpopulation of patients with growth through mechanisms depending on the induction non-small cell lung cancer lacking neuroendocrine cells of protease nexin-1, a serine protease inhibitor endowed in tumor tissues and in cancer patients treated with proton of anti-angiogenic activity. pump inhibitors, a class of drugs commonly used to treat acid peptic disorders [8-11]. Furthermore, elevated serum RESULTS levels of CgA have been observed in patients with renal failure, heart failure, hypertension, rheumatoid arthritis, atrophic gastritis, inflammatory bowel disease, sepsis Exogenous CgA exerts anti-tumor effects with and other inflammatory diseases [1, 2, 8, 12-23]. Using U-shaped dose-response curves in various murine specific assays, we recently observed that CgA is present models in the blood of normal subjects and cancer patients as a mixture of full-length protein and fragments, including the N-terminal fragment CgA1-76 (vasostatin-1) and other The effect of exogenous recombinant and natural fragments lacking part or the entire C-terminal region [24, CgA (produced in E.coli cells and purified from 25]. Interestingly, the plasma levels of the fragment CgA1- pheochromocytomas, respectively) on tumor growth 373, which is not or minimally present in normal subjects, was investigated in different murine models, including is increased in the peripheral blood (and even more in the WEHI-164 fibrosarcoma, TSA adenocarcinoma B16-F1 bone marrow plasma) of patients with multiple myeloma, melanoma, and Lewis lung carcinoma (LLC), implanted while full-length CgA is decreased, pointing to increased subcutaneously in syngeneic mice. Furthermore, a CgA C-terminal fragmentation in these patients [25]. metastasis model based on lung colonization by B16-F10 Thus, variable levels of full-length CgA and fragments melanoma cells injected intravenously in mice was are present in the blood of cancer patients for a variety also used. Administration of 6 to 30 pmol of human of reasons. recombinant full-length CgA to WEHI-164-bearing mice A central question that we have yet to answer is (i.p., every 3-4 days, three times) significantly delayed whether the neuroendocrine release of CgA in circulation the growth of subcutaneous tumors in a dose-dependent and its fragmentation can affect the biology and manner (Figure 1A, upper panels). However, increasing progression of non-neuroendocrine tumors. the dose to 150 pmol resulted, paradoxically, in a lower Interestingly, recent studies have shown that effect (Figure 1A, lower panels). U-shaped dose response CgA1-439 and the N-terminal fragment CgA1-76 inhibit curves were also observed in the TS/A and B16-F1 angiogenesis, whereas the fragment CgA1-373 stimulates subcutaneous models, after treatment (i.p.) with 0, 30, angiogenesis in various angiogenesis assays [24, 26]. 90 or 0, 30, 740 pmol of recombinant CgA, respectively Furthermore, full-length CgA1-439 and CgA1-78 can protect (Figure 1B and 1C) as well as in the B16-F10 lung- the endothelial barrier from the disassembly of vascular colonization model, after treatment (i.v.) with 0, 4, 20 endothelial-cadherin adherence junctions, gap formation, and 100 pmol of CgA (Figure 1D). Of note, the 740 pmol and vascular leakage [27, 28], and reduce the traffic of dose, which was aimed at exploring an extremely high tumor cells through the endothelium [29]. Although these concentration of CgA, was completely inactive. findings suggest that CgA and some of its fragments might Recombinant and natural CgA (30 pmol, i.p.) affect tumor biology, the pathophysiological relevance of exerted similar effects in the WEHI-164 and LLC models circulating full-length CgA and the potential impact of (Suppl. Figure S1). Furthermore, decreasing the dose to CgA fragmentation on tumor progression remains to be 6 pmol reduced the anti-tumor effects in both cases (not established. shown). Thus, natural CgA and recombinant CgA exerted These notions prompted us to explore the potential similar anti-tumor effects in these models. role of circulating CgA as a regulator of tumor growth. Optimal activity in all subcutaneous models was As vascularized tumors are exposed to CgA released in achieved with i.p. injection of 30 pmol of CgA (Figure circulation by the neuroendocrine system, we decided to 1A-1C), whereas i.v. injection of the same dose was less perform the study using various murine models of non- effective (data not shown). Pharmacokinetic analysis neuroendocrine solid tumors, including subcutaneous showed that the i.p. route generated circulating peak levels www.impactjournals.com/oncotarget 72717 Oncotarget of about 3-4 nM CgA, whereas the i.v. route generated The C-terminal region of CgA (residues 410-439) 17 nM levels (Suppl. Figure S2). This may explain the is crucial for its anti-tumor activity paradoxical lower activity of the i.v. versus the i.p. route. Accordingly, in the lung-colonization model, which was based on i.v. administration, maximal activity was We have previously shown that
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