Frequent co-expression of EGFR and NeuGcGM3 ganglioside in cancer: it’s potential therapeutic implications

Clinical & Experimental Metastasis, Jul 2016

Interaction between epidermal growth factor receptor (EGFR) signaling with GM3 ganglioside expression has been previously described. However, little is known about EGFR and NeuGcGM3 co-expression in cancer patients and their therapeutic implications. In this paper, we evaluate the co-expression of EGFR and NeuGcGM3 ganglioside in tumors from 92 patients and in two spontaneous lung metastasis models of mice (Lewis lung carcinoma (3LL-D122) in C57BL/6 and mammary carcinoma (4T1) in BALB/c). As results, co-expression of EGFR and NeuGcGM3 ganglioside was frequently observed in 63 of 92 patients (68 %), independently of histological subtype. Moreover, EGFR is co-expressed with NeuGcGM3 ganglioside in the metastasis of 3LL-D122 and 4T1 murine models. Such dual expression appears to be therapeutically relevant, since combined therapy with mAbs against these two molecules synergistically increase the survival of mice treated. Overall, our results suggest that NeuGcGM3 and EGFR may coordinately contribute to the tumor cell biology and that therapeutic combinations against these two targets might be a valid strategy to explore.

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Frequent co-expression of EGFR and NeuGcGM3 ganglioside in cancer: it’s potential therapeutic implications

Clin Exp Metastasis Frequent co-expression of EGFR and NeuGcGM3 ganglioside in cancer: it's potential therapeutic implications Addys Gonza´lez Palomo 0 1 2 3 Rance´s Blanco Santana 0 1 2 3 Xiomara Escobar Pe´rez 0 1 2 3 Damia´n Blanco Santana 0 1 2 3 Mariano Rolando Gabri 0 1 2 3 Kalet Leo´n Monzon 0 1 2 3 Adriana Carr Pe´rez 0 1 2 3 0 Department of Cell Biology and Tissues Banking, National Institute of Oncology and Radiology , 29 and F Street, Vedado, Plaza de la Revolucio ́n, P.O. Box 10400, Havana , Cuba 1 Center of Molecular Immunology (CIM) , 216 Street and 15 Avenue, Atabey, Playa, P.O. Box 16040, Habana , Cuba 2 & Addys Gonza ́lez Palomo 3 Laboratory of Molecular Oncology, Quilmes National University , R. Sa ́enz Pen ̃a 180, P.O. Box B1876BXD, Buenos Aires , Argentina Interaction between epidermal growth factor receptor (EGFR) signaling with GM3 ganglioside expression has been previously described. However, little is known about EGFR and NeuGcGM3 co-expression in cancer patients and their therapeutic implications. In this paper, we evaluate the co-expression of EGFR and NeuGcGM3 ganglioside in tumors from 92 patients and in two spontaneous lung metastasis models of mice (Lewis lung carcinoma (3LL-D122) in C57BL/6 and mammary carcinoma (4T1) in BALB/c). As results, co-expression of EGFR and NeuGcGM3 ganglioside was frequently observed in 63 of 92 patients (68 %), independently of histological subtype. Moreover, EGFR is co-expressed with NeuGcGM3 ganglioside in the metastasis of 3LLD122 and 4T1 murine models. Such dual expression appears to be therapeutically relevant, since combined therapy with mAbs against these two molecules synergistically increase the survival of mice treated. Overall, our results suggest that NeuGcGM3 and EGFR may Addys Gonza´lez Palomo and Rance´s Blanco Santana have equally contributed to this work. Kalet Leo´n Monzon and Adriana Carr Pe´rez co-supervised this work. EGFR; NeuGcGM3 Co-expression Pulmonary metastasis Combination therapy - Most epithelial tumors overexpress the EGFR and their activation is related with cancer progression. However, tumors exhibit a diverse response to anti-EGFR therapies, with resistance as common result of the treatment [1]. The N-Acetylneuramic acid (NeuAcGM3) ganglioside, but not the N-glycolylneuramic acid (NeuGcGM3), is usually detected in normal human tissues. However, many human tumors express NeuGcGM3 ganglioside [2–7]. The expression of NeuGcGM3 have been associated with a worse prognosis in colon [8] and lung cancer [7, 9]. Differential association between EGFR signaling pathway and GM3 ganglioside expression has been reported [10–13]. Overexpression of GM3 increase the proliferation of carcinoma cells (A431) by ERK-independent signaling, in the presence of urokinase plasminogen activator (uPA) and their receptor (uPAr) [14]. Conversely, GM3 depletion increase the EGFR phosphorylation and the ERK-dependent cell proliferation becomes prevalent [14]. These results provide a rational for a combined treatment targeting simultaneously both EGFR and GM3 mediated signaling pathways. The Center of Molecular Immunology (CIM, Havana, Cuba) have developed several immunotherapeutic projects targeting separately both EGFR [15, 16] and NeuGcGM3 [17, 18]. Therefore, we evaluate the frequency of coexpression of EGFR and NeuGcGM3 ganglioside in human tumors and in two spontaneous lung metastasis models of mice (Lewis lung carcinoma (3LL-D122) in C57BL/6 and mammary carcinoma (4T1) in BALB/c). Moreover, we perform an initial evaluation of the therapeutic implications of targeting simultaneously both molecules, in lung models. Materials and methods Patients samples Sections of formalin-fixed and paraffin-embedded tumor tissues from 92 patients were taken from the pathology department of the National Institute of Oncology and Radiobiology and Dr. ¨Manuel Fajardo¨ General Teaching Hospital after receiving approved consent by the Ethical Committee of the institute. Lewis lung carcinoma (3LL-D122); mouse breast adenocarcinoma cells (4T1); human vulva epidermoid carcinoma (A431, ATCC, CRL-1555) and murine myeloma P3-X63Ag8.653 (X63, ATCC, CRL-1580) were cultured in DMEM: F12 (Life Technologies Inc., Grand Islan, NY) supplemented with 10 % fetal bovine serum (FBS). Lung metastasis murine models Mice female of 6–8 week old female, were purchased from the Center for Laboratory Animal Production (CENPALAB, Havana, Cuba). Animal’s procedures were performed in accordance with the guidelines stipulated by Animal Subject Committee Review Board of the CIM and CIM’’s Institutional Animal Care and Use Committees. 3LL-D122-metastasis model: C57BL/6 mice were injected into lateral tail veins (i.v.) with 2.5 9 105 of tumor cells. 4T1-metastasis model: BALB/c mice were transplanted subcutaneously (s.c). into the mammary gland with 1 9 104 of tumor cells. Primary tumor diameters were measured every 2–3 days with a caliper and tumor volume (mm3) was determined to t (...truncated)


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Addys González Palomo, Rancés Blanco Santana, Xiomara Escobar Pérez, Damián Blanco Santana, Mariano Rolando Gabri, Kalet León Monzon, Adriana Carr Pérez. Frequent co-expression of EGFR and NeuGcGM3 ganglioside in cancer: it’s potential therapeutic implications, Clinical & Experimental Metastasis, 2016, pp. 717-725, Volume 33, Issue 7, DOI: 10.1007/s10585-016-9811-0