A rebuttal to the potential anti-tumour benefit of Helicobacter pylori-induced neutrophil-activating protein

Dear Editors,

In their paper, Codolo et al. [1] concluded that Helicobacter pylori (HP) neutrophil-activating protein (HP-NAP), by activating a cytotoxic T helper (Th) 1 response, inhibits the growth of bladder cancer in mice, findings strongly indicating that HP-NAP might become a novel therapeutic ‘bullet’ for the cure of bladder tumours. However, their remarks raise some concerns.

Although HP-NAP plays a major role in generating and maintaining the HP-associated gastric inflammatory response and, moreover, HP-NAP is a promising vaccine candidate against HP infection (HP-I), concerns regarding its potential drawbacks, particularly neurogenic ones, should be considered before, as the authors considered [1], in vivo studies to assess the HP-NAP anti-tumour efficacy in humans are conducted. For instance, possible cross-mimicry between HP-NAP and/or bacterial aquaporin (AQP) and neural tissues may be associated with the anti-AQP-4 antibody-related neural damage in multiple sclerosis (MS)/neuromyelitis optica (NMO) patients [2, 3]. In this respect, using histology, recognised as the practical gold standard for the diagnosis of current HP-I, we showed a strong association between HP-I and MS in a Greek cohort [4]. Current HP-I induces irregular humoral and cellular immune responses that, owing to the sharing of homologous epitopes (i.e. molecular mimicry), cross-react with components of nerves, thereby constantly triggering and possibly perpetuating neural tissue damage observed in neurodegenerative diseases [5, 6]. In this regard, HP virulence factors promote the release of various chemoattractants/inflammatory mediators including interleukin (IL)-8, IL-12 or interferon (IFN)-γ, mentioned by the authors, and HP-NAP, which, as a virulence factor, recruits leucocytes from the vascular lumen, activates neutrophils, monocytes and mast cells [2, 5, 7, 8]. Specifically, a series of factors have been implicated in inducing blood–brain barrier (BBB)/blood nervous barrier (BNB) disruption, including the aforementioned inflammatory mediators (e.g. cytokines and chemokines induced by HP-I) and oxidative stress [9]. They increase vascular permeability and BBB/BNB disruption [tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), vascular permeability factor], induce transmigration of leucocytes into the nerve, activation and proliferation of macrophages (IFN-γ) and T cells (ΙL-1, IL-2) and exert direct myelinotoxic activities (TNF-α and TNF-β). In this respect, Schwann cell induces reactivation of CD4+ T cells, which, by producing TNF-α and IFN-γ, could exacerbate BNB disruption thus playing a role in neuropathies. Intraneural activated T cells cause focal BNB disruption, and, moreover, increased circulating TNF-α might play a role in the ΒΒΒ/BNB disruption and the pathogenesis of demyelination; HP through the release of TNF-α, acting at distance, is involved in BBB/BNB disruption through a mechanism involving matrix metalloproteinase upregulation [9, 10]. HP-NAP induces a strong Th1 response, mentioned by the authors [1], a predominant HP-specific Th1 response is characterised by a high TNF-α, IFN-γ, IL-2 and IL-12 production leading to apoptotic damage and the Th1 type cytokine TNF-α leads to TNF-α-related apoptotic neuronal cell death in neurodegenerative diseases including, for instance, Alzheimer’s disease [11]. In addition, apart from activated mast cells, VEGF, IL-8, chymase or tryptase (a serine endoprotease released by mast cells) and mast cell growth factor linked to HP-Ι and HP-NAP, mast cells themselves can be stimulated by corticotropin-releasing hormone, secreted under stress, to release mediators including histamine, IL-8, tryptase and VEGF, which disrupt the BBB/BNB [9, 10]. In turn, ΒΒB/BNB breakdown could promote entry of immune cell (autoreactive effector CD4+ and CD8+ T cells) infiltrations, activated monocytes infected with HP, due to defective autophagy resulting in HP-Ι replication in autophagic vesicles and/or HP circulating antibodies into the peripheral and central neurons resulting in the development of neuronal pathologies [9]. Mast cells are located in close proximity to neurons in the peripheral and central nervous systems, signifying their role in normal and aberrant neurodegenerative conditions [9]. Mast cell degranulation is able to secrete potent mediators which could orchestrate neuroinflammation and affect the BBB/BNB integrity, thereby playing a role in neuropathies [9]; BBB disruption permits access of AQP4-specific antibodies and T lymphocytes to the central nervous system, playing a major role in MS/NMO pathogenesis [3]. Therefore, HP-NAP and HP-I itself, by inducing several mediators, may influence the pathophysiology of neurodegenerative diseases, thus raising possible concerns regarding the HP-NAP use as a candidate anti-tumour agent. Nevertheless, relative studies are needed to clarify the aforementioned concerns.

HP is classified as class I carcinogen, and HP-NAP may play a role in gastrointestinal oncogenesis; HP-NAP antibodies are significantly higher in gastric cancer patients indicating a possible pathogenetic role of HP-NAP in gastric carcinogenesis [12]. Specifically, HP-NAP may contribute to inflammatory response or carcinogenesis by activating neutrophils, which induce the production of reactive oxygen species (ROS) [12]; ROS can cause a variety of DNA lesions, and they can produce mutations in bacterial and mammalian cells and also induce malignant transformation in cultured fibroblast cell lines [7]. Since HP-NAP is a potent stimulant for the production of ROS, mediating damage to DNA and enhancing cell turnover, it appears to be a risk factor for HP-associated gastric cancer [12]. Apart from neutrophils and monocytes, HP-NAP also activates mast cells [2, 13], and mast cells can be stimulated by corticotropin-releasing hormone, secreted under stress, to release the mentioned mediators which disrupt the BBB permitting metastases of lung and mammary adenocarcinomas [14]. In this regard, HP-I appears to be a common denominator of lung, mammary and gastrointestinal tract cancers contributing to the mentioned stress–mast cell–BBB disruption–brain metastases sequence of these malignancies [8].

In view of the aforementioned data, further relative investigation might be important to assess the potential concerns of HP-NAP before using it as an innovative therapeutic regimen for the cure of bladder cancer in humans.