WEHI researchers have identified a key molecular regulator involved in the progression and spread of stomach cancer, suggesting a potential new approach to treat this devastating disease.
The team discovered that removing the inflammatory signaling protein TNF in a laboratory model prevented early stage stomach cancers from progressing to a more severe stage that, in humans, is much harder to treat.
This discovery suggests that stomach cancers may respond to medicines that inhibit TNF.
Of note, drugs that inhibit TNF have already shown success in the clinic for certain other diseases, particularly rheumatoid arthritis.
The research, published in the journal Gastroenterology, was led by Dr. Lorraine O’Reilly, Dr. Tracy Putoczki, Professor Andreas Strasser, Dr. Jun Ting Low and Dr. Michael Christie, who is also a clinical pathologist at The Royal Melbourne Hospital.
Pinpointing the culprits
More than one million people around the world – including more than 2000 Australians – are diagnosed with stomach cancer each year.
This cancer is often detected late, at hard-to-treat stages, with fewer than one-third of Australians with stomach cancer surviving for five years after their diagnosis.
Understanding which factors are important for stomach cancer to develop and progress to invasive stages could lead to much-needed better treatments.
To do this, the research team used a laboratory model of stomach cancer that they had developed, Dr. O’Reilly said.
“Human stomach cancer can be caused by prolonged inflammation and our model of stomach cancer, that is driven by the absence of the protein NF-KB1, accurately reflects the sequential changes seen in human stomach cancer as it progresses from an early, inflammatory stage.
“We discovered that invasive stomach cancers contain high levels of various factors involved in inflammation, including four soluble proteins called cytokines.
“By removing each of the four cytokines that were elevated in our model, we could assess how important each one was. This revealed that the cytokine TNF was required for the progression of stomach cancer,” she said.
Potential new therapies
The discovery that TNF is a critical driver of stomach cancer development raised the possibility of this cytokine being a potential therapeutic target, Dr. Putoczki said.
“Many therapies have shown great promise in treating inflammatory diseases by targeting specific cytokines,” she said. “Excitingly, there are already medicines in clinical use that block TNF, most notably for the treatment of rheumatoid arthritis.
“Our research suggests these therapies could be an effective and safe way to prevent the progression of stomach cancer to more severe, invasive forms. This is an area we are looking at in more detail.”
Ulcerative colitis (UC) and Crohn’s disease (CD) are immune-mediated types of inflammatory bowel diseases (IBD) affecting the gastrointestinal tract (GIT). IBD is a chronic disease with a course characterized by remission and relapse. Disease symptoms include chronic diarrhea, abdominal pain, weight loss and bloody stools.
The severity combined with the chronic nature of the disease results in a decreased health-related quality of life, disability and frequent hospitalizations. Whereas the continuous and diffuse inflammation of the mucosa in UC is typically limited to the rectum and may extent proximally, the granulomatous transmural inflammation in CD affect most commonly the ileo-colonic region [1,2,3].
Although the exact pathogenesis of IBD is unclear, research shows that a combination of genetics, environmental factors and the microbiome play a prominent role in the onset of gut epithelial dysfunction. Consequently, increased exposure of the gut wall to luminal antigens trigger an aberrant acute inflammatory response driven by the innate immune system.
Secretion of proinflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) results not only in tissue damage, but the activation of the adaptive immune system as well. Tissue damage in turn may result in an increased exposure of the gut wall to luminal antigens inducing a stronger activation of both the innate and adaptive immune system, which perpetuates the inflammatory state resulting in chronic inflammation (Figure 1) [2,3,4,5,6,7].
TNF-α is a pleiotropic proinflammatory cytokine implicated in a wide range of cellular processes including cell proliferation, survival and death. In addition, TNF-α signaling is associated with the regulation of several inflammatory pathways including the cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) pathways [8,9,10,11].
Hence, TNF-α is a key mediator in the inflammatory response. TNF-α is predominantly secreted by monocytes, macrophages and natural killer cells [12,13,14,15,16]. TNF-α is first synthesized as a transmembrane protein (tmTNF-α) and can induce immunological responses in effector cells, but also transduce reverse signaling by contact-dependent cell interactions.
In addition, tmTNF-α can be enzymatically cleaved by TNF-α-converting enzyme (TACE) resulting in soluble TNF-α (sTNF-α). Upon distribution in the extracellular space or systemic circulation, sTNF-α may exert immunological effects at distant sites. Therefore, both forms are active cytokines that share similar as well as distinctive immunological effects.
TNF-α activation of effector cells under physiological conditions generally leads to a proinflammatory response or apoptosis and aids in the defense against infections and localized tissue injury [12,13,14,15,16]. However, the elevated TNF-α tissue levels in the mucosa and lamina propria of IBD patients result in an aberrant proinflammatory response that is associated with the dysregulation of mucosal immune cells and tissue damage [4,7].
Anti-TNF-α therapy aims to antagonize the effects of TNF-α.
Examples of anti-TNF-α therapies which are or have been used in the clinical setting of IBD are infliximab (IFX), adalimumab, golimumab, certolizumab, etanercept, onercept and CDP571 (Figure 2).
These biologicals are antibodies or soluble TNF-α receptors (sTNFR) that neutralize TNF-α. Although the main mechanism of action is TNF-α antagonism, these drugs have distinctive pharmacodynamic profiles that are specific for the individual compound partly due to the variations in the molecular structure. Hence, the observed efficacy of the different anti-TNF-α therapies in IBD vary and are not equivalent (reviewed in: [13,17,18,19,20,21,22]).
The desired therapeutic effects include a sustained anti-inflammatory response, mucosal healing and restoration of the gut epithelial barrier function [23,24]. However, anti-TNF-α therapy is associated with adverse events related to systemic exposure.
These adverse events include infusion reactions [25,26], psoriasis or psoriasiform lesions , osteonecrosis of the jaw [28,29], the development of antinuclear antibodies (ANA) [30,31,32,33] and an increased risk of opportunistic infections [34,35,36] and developing lymphoma . Additionally, infusion reactions are associated with therapy discontinuation . Systemic administration may induce anti-drug antibodies (ADA), which in turn is associated with infusion reactions as well as loss of efficacy [39,40,41].
Research shows that the local immunological environment in the GIT correlates with IBD disease activity [42,43,44,45], type [46,47,48] and relapse [49,50]. Furthermore, studies investigating the local immunological environment of the GIT before and after anti-TNF-α therapy show that the therapy reduces histological and endoscopical disease activity [51,52,53], inhibits activation of immune cells [54,55,56], downregulates the expression of cell adhesion molecules and proinflammatory cytokines [53,57,58,59,60,61,62], modulates apoptosis of monocytes as well as enterocytes , restores gut barrier function [64,65] and levels of antimicrobial peptides  and has a favorable effect on the gut microbiome [67,68,69].
Importantly, it was shown that anti-TNF-α therapy induces a potent local, but not a systemic effect  and that gut tissue concentrations may correlate better with a clinical and sustained response compared to serum levels alone [71,72]. This may partly explain anti-TNF-α therapy failure despite therapeutic drug concentrations.
Collectively these observations suggest that local as opposed to systemic TNF-α inhibition may be an efficacious treatment option for IBD which may have fewer adverse events related to systemic exposure. However, major challenges in accomplishing site-specific TNF-α inhibition with macromolecules such as proteins are drug targeting and the subsequent stability of the drug in the GIT.
More important, drug penetration into the targeted inflamed sites is a prerequisite for drug efficacy, but may arguably impose the biggest challenge since the absorption mechanisms and kinetics of macromolecules differ substantially from smaller chemical entities [73,74,75,76,77,78].
The objective of this narrative review was to evaluate the available literature on PubMed with regards to local TNF-α inhibition in IBD. First, animal studies investigating the efficacy or feasibility of local TNF-α inhibition in IBD are discussed. These studies investigated formulations containing antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms.
Subsequently, clinical studies ranging from case reports to randomized placebo-controlled clinical trials that investigated the efficacy or feasibility of local TNF-α inhibition in IBD are discussed. This review aims to summarize the available literature on local TNF-α inhibition with macromolecules intended for the treatment of IBD.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356880/
More information: Jun T. Low et al. Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice, Gastroenterology (2020). DOI: 10.1053/j.gastro.2020.06.039