Alpha 1‐antitrypsin: A novel tumor‐associated antigen identified in patients with early‐stage breast cancer

López-Árias, Eneida; Aguilar‐Lemarroy, Adriana; Jave‐Suárez, Luis Felipe; Morgan-Villela, Gilberto; Mariscal-Ramírez, Ignacio; Martínez-Velázquez, Moisés; Álvarez, Ángel H.; Gutiérrez-Ortega, Abel; Gutiérrez, Rodolfo Hernández

doi:10.1002/elps.201100491

Cited by 36 publications

(30 citation statements)

References 36 publications

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“…They are biochemically well-characterized, and many reagents and techniques are available for their detection, simplifying assay development. Until very recently, several specific autoantibodies have been detected in the sera of patients with advanced-stage breast cancer (14,(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58). However, very few studies have attempted to identify and/or evaluate autoantibodies in node-negative earlystage PBC ( 2 cm) or, more importantly, in preinvasive breast cancer, for which mammography's sensitivity is decreased.…”

Section: Discussionmentioning

confidence: 99%

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

Lacombe

Mangé

Bougnoux

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging.Methods: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2). Circulating autoantibody levels were measured in a cohort of 396 serum samples from histologically confirmed DCIS (n ¼ 87) or T1N0 PBC (n ¼ 153) and healthy controls (n ¼ 156).Results: Individually, antibodies against CCNB1, FKBP52, GAL3, PAK2, PRDX2, PPIA, P53, and MUC1 demonstrated discriminatory power between breast cancer and healthy control groups. At 90% sensitivity, the overall combined specificity of the autoantibody serum screening test was 42%. Adjustment for higher sensitivities of 95% and 99% resulted in 30% and 21% specificities, respectively (33% and 18% in T1N0 PBC and 28% and 21% in DCIS). Finally, in patients with node-negative early-stage breast cancer younger than 50 years, the autoantibody assay exhibited 59% specificity with a fixed sensitivity at 90%.Conclusions: Our autoantibody panel allows accurate detection of early breast cancer and DCIS, notably in younger patients.Impact: Clinical assessment of this autoantibody panel displays a potential to facilitate clinical management of early-stage breast cancer detection in cases of inconclusive mammogram. Cancer Epidemiol Biomarkers Prev; 23(9); 1834-42. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

Lacombe

Mangé

Bougnoux

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…On the one hand, a rise in serum levels of AAT and other acute-phase proteins has been documented in various forms and stages of cancer, including hepatocellular carcinoma [28], lung cancer [29,30], GI tract tumors [31], breast cancer [32], pancreatic cancer [33] and urinary bladder cancer [34]; on the other hand, these might represent the inflammatory response of a disease-stricken body. Similarly, in some cases, a positive correlation between serum or local AAT levels and tumor progression can be documented, alongside a negative prognosis.…”

Section: Cancer and Circulating Aat: Is There An Apparent Association?mentioning

confidence: 99%

Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology

Guttman¹,

Freixo-Lima²,

Lewis³

2016

Integr Cancer Sci Therap

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The acute-phase protein α1-antirypsin (AAT) has recently been suggested to exert beneficial effects in various immune-associated pathologies, such as graftversus-host disease, rheumatoid arthritis, multiple sclerosis and allogeneic transplantation. These effects have been demonstrated to take place through direct immunomodulation of dendritic cells, macrophages, neutrophils and B cells, while allowing, in a yet inexplicable distinction, intact isolated functions of T cells and NK cells. With such a unique discriminatory targeting of immunocytes, AAT drives immune responses simultaneously towards regulation of inflammation and expansion of antigen-specific regulatory T cells (Tregs). Based on this intriguing activity profile, a concern was raised regarding the impact of chronic treatment with human AAT with respect to susceptibility to tumors and to metastatic spread. Tumor development is linked to inflammatory responses in a manner which largely promotes immune evasion. Local innate immunocytes, such as tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs) and the recently appreciated tumor-associated neutrophils (TANs), are considered instrumental in primary tumor survival. This is accomplished in part by the release of growth factors and cytokines, including VEGF, TGFβ, IL-10 and IL-1 receptor antagonist (IL-1Ra), all of which have been demonstrated to be elevated in inflammatory conditions during AAT therapy. While clinical studies report heightened serum AAT levels in patients with a variety of advanced tumors, there is no evidence to point to a particular pro-tumor effect of AAT, and the possibility that its elevation in the blood might represent a meresystemic marker-rather than an accessory to tumor development-is grossly overlooked. Indeed, preclinical studies reveal significant inhibition of tumor development during treatment with AAT, and prolonged follow-up studies of individuals who receive life-long excessive doses of intravenous AAT do not depict a rise in tumor occurrence. Considering the prospect of AAT being indicated for medical indications to individuals with normal levels of the protein, its relation to tumor immunology is of immense importance. We hereby review the current knowledge regarding some possible roles that AAT may play, both locally and systemically, in the delicate and detrimental arena of tumor immunology.

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“…However, a few of these proteins listed in Table 3 are related to pro-cancer or anti-cancer properties to cancer cells [65][66][67][68][69][70][71][72][73][74]. The molecular nature and functions of these captured human serum proteins remain to be explored in the future [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68].…”

Section: Human Serum Proteins Recognized Separately By Ca215 and Ciggmentioning

confidence: 99%

Dual Differential Roles of Cancerous Immunoglobulins as Suggested by Interactions with Human Serum Proteins

Lee¹

2015

J Clin Cell Immunol

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In search of functional roles of immunoglobulins expressed by cancer cells, molecular interactions between cancerous immunoglobulins and human serum proteins or protein fragments were investigated by using RP215 monoclonal antibody as the unique probe. RP215 was initially generated against OC-3-VGH ovarian cancer cell extract and shown to react with carbohydrate-associated epitope located mainly on the variable regions of immunoglobulin heavy chains and others expressed by cancer cells which are designated in general as CA215. CA215 and cancerous immunoglobulins (cIgG) were affinity isolated from the shed medium of cultured cancer cells. Furthermore, by using purified CA215 and cIgG as the respective affinity ligands, the serum proteins or components were affinity isolated and subject to analysis by LCMS/MS methods. The results of such analysis suggest that as many as 80-86% of the isolated human serum proteins were identical in those purified by either affinity column. They are generally classified as pro-cancer and anti-cancer protein components. Among the known pro-cancer protein components recognized by cancerous immunoglobulins are C4 binding proteins α-chain, complement C3, complement factor H, serotransferrin and vitronectin, etc. On the other hand, inter-α-trypsin inhibitor heavy chain 4, anastellin, apolipoprotein A1, fibrinogen β-chain and keratin type 1 cytoskeletal 9 or autoimmune IgG were considered to be anti-cancer proteins from human serum. Based on these observations, dual functional roles of cancerous immunoglobulins are hypothesized. It has been demonstrated in this study that cancerous immunoglobulins are capable of serving as specific binding protein-like immunoglobulins to capture serum proteins to promote growth of cancer cells. At the same time, they can neutralize those with anti-cancer properties in human circulations.

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Alpha 1‐antitrypsin: A novel tumor‐associated antigen identified in patients with early‐stage breast cancer

Cited by 36 publications

References 36 publications

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology

Dual Differential Roles of Cancerous Immunoglobulins as Suggested by Interactions with Human Serum Proteins

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