Gastric Intestinal Metaplasia: Challenges and the Opportunity for Precision Prevention.

GIM is a persistent, premalignant lesion whereby gastric mucosa is replaced by metaplastic mucosa resembling intestinal tissue, arising in the setting of chronic inflammation, particularly in the context of Helicobacter pylori. While the overall rates of progression to gastric adenocarcinoma are low, estimated at from 0.25 to 2.5%, there are features that confer a much higher risk and warrant follow-up. In this review, we collate and summarise the current knowledge regarding the pathogenesis of GIM, and the clinical, endoscopic and histologic risk factors for cancer. We examine the current state-of-practice with regard to the diagnosis and management of GIM, which varies widely in the published guidelines and in practice. We consider the emerging evidence in population studies, artificial intelligence and molecular markers, which will guide future models of care. The ultimate goal is to increase the detection of early gastric dysplasia/neoplasia that can be cured while avoiding unnecessary surveillance in very low-risk individuals.

CD10 and Das1: a biomarker study using immunohistochemistry to subtype gastric intestinal metaplasia.

BACKGROUND: Intestinal metaplasia (IM) is considered a key pivot point in the Correa model of gastric cancer (GC). It is histologically subtyped into the complete and incomplete subtypes, the latter being associated with a greater risk of progression. However, the clinical utility of IM subtyping remains unclear, partially due to the absence of reliable defining biomarkers. METHODS: Based on gene expression data and existing literature, we selected CD10 and Das1 as candidate biomarkers to distinguish complete and incomplete IM glands in tissues from patients without GC (IM-GC) and patients with GC (IM + GC). Immunohistochemical staining of individually subtyped IM glands was scored after blinding by two researchers using tissue belonging to both IM-GC and IM + GC patients. Whole tissue Das1 staining was further assessed using digital image quantification (cellSens Dimension, Olympus). RESULTS: Across both cohorts CD10 stained the IM brush border and was shown to have a high sensitivity (87.5% and 94.9% in IM-GC and IM + GC patients respectively) and specificity (100.0% and 96.7% respectively) with an overall AUROC of 0.944 for complete IM glands. By contrast Das1 stained mainly goblet cells and the apical membrane of epithelial cells, mostly of incomplete IM glands with a low sensitivity (28.6% and 29.3% in IM-GC and IM + GC patients respectively) but high specificity (98.3% and 85.1% respectively) and an overall AUROC of 0.603 for incomplete IM glands. A combined logistic regression model showed a significant increase in AUROC for detecting complete IM glands (0.955 vs 0.970). Whole tissue digital quantification of Das1 staining showed a significant association with incomplete IM compared to complete IM, both in IM-GC and in IM + GC patients (p = 0.016 and p = 0.009 respectively, Mann-Whitney test and unpaired t test used). Additionally, complete IM in IM + GC patients exhibited significantly more Das1 staining than in IM-GC patients (p = 0.019, Mann-Whitney test). CONCLUSIONS: These findings suggest that CD10 is an outstanding biomarker for complete IM and Das1 may be useful as a secondary biomarker for IM glands at greater risk of progression irrespective of IM subtype. Overall, the clinical use of these biomarkers could lead to improved patient stratification and targeted surveillance.

The Role of Innate Immune Cells in Tumor Invasion and Metastasis.

Metastasis is considered one of the hallmarks of cancer and enhanced tumor invasion and metastasis is significantly associated with cancer mortality. Metastasis occurs via a series of integrated processes involving tumor cells and the tumor microenvironment. The innate immune components of the microenvironment have been shown to engage with tumor cells and not only regulate their proliferation and survival, but also modulate the surrounding environment to enable cancer progression. In the era of immune therapies, it is critical to understand how different innate immune cell populations are involved in this process. This review summarizes recent literature describing the roles of innate immune cells during the tumor metastatic cascade.

SFRP4 drives invasion in gastric cancer and is an early predictor of recurrence.

OBJECTIVE: Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence. DESIGN: Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection. RESULTS: Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed PredictR. CONCLUSIONS: This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection.

A cohort study and meta-analysis of the evidence for consideration of Lauren subtype when prescribing adjuvant or palliative chemotherapy for gastric cancer.

BACKGROUND: The association between the survival or efficacy of chemotherapy and the Lauren subtype of gastric cancer (GC) remains unclear. We aimed to clarify whether patients with different Lauren subtypes have different survival after treatment with systemic chemotherapy: intestinal gastric cancer (IGC) patients survived better than patients with mixed type gastric cancer (MGC) or diffuse gastric cancer (DGC) after treatment with systemic chemotherapy. PATIENTS & METHODS: Relevant studies for the meta-analysis were identified through searching Pubmed, Embase, Cochrane and Ovid up to March 2020. We also included our own prospectively collected cohort of patients that were followed over a 10-year period. Sub-group and sensitivity analyses were also performed. RESULTS: In our prospective cohort, the overall survival (OS) of IGC patients receiving systemic chemotherapy (chemoIGC) [median OS 5.01 years, interquartile range (IQR) 2.63-6.71] was significantly higher than that of DGC patients receiving the same chemotherapy (chemoDGC) (median OS 1.33 years, IQR 0.78-3.33, p = 0.0001). After adjusting for age, gender and cancer stage, there was a significant difference in OS in patients treated with chemotherapy based on the Lauren classification of GC {hazard ratio (HR) for OS of the IGC versus DGC 0.33, [95% confidence interval (CI), 0.17-0.65; p < 0.001]}. In the IGC patients, the adjusted HR associated with chemotherapy was 0.26 (95% CI, 0.12-0.56; p = 0.001), whereas the association was 0.64 (95% CI, 0.30-1.33; p = 0.23) in the DGC patient group.In our meta-analysis, 33 studies comprising 10,246 patients treated with systemic chemotherapy (chemoIGC n = 4888, chemoDGC n = 5358) met all the selection criteria. While we accounted for much of the heterogeneity in these studies, we found that chemoIGC patients showed significantly improved OS [HR, 0.76 (95% CI, 0.71-0.82); p < 0.00001] when compared with similarly treated chemoDGC patients. CONCLUSION: Our results support the consideration of Lauren subtype when prescribing systemic chemotherapy for GC, particularly for MGC or DGC, which may not benefit from chemotherapy. Lauren classification should be considered to stratify chemotherapy regimens to GC patients in future clinical trials, with particular relevance to MGC or DGC, which is more difficult to treat with current regimens.

High-dimensional analyses reveal a distinct role of T-cell subsets in the immune microenvironment of gastric cancer.

OBJECTIVES: To facilitate disease prognosis and improve precise immunotherapy of gastric cancer (GC) patients, a comprehensive study integrating immune cellular and molecular analyses on tumor tissues and peripheral blood was performed. METHODS: The association of GC patients' outcomes and the immune context of their tumors was explored using multiplex immunohistochemistry (mIHC) and transcriptome profiling. Potential immune dysfunction mechanism/s in the tumors on the systemic level was further examined using mass cytometry (CyTOF) in complementary peripheral blood from selected patients. GC cohorts with mIHC and gene expression profiling data were also used as validation cohorts. RESULTS: Increased CD4+FOXP3+ T-cell density in the GC tumor correlated with prolonged survival. Interestingly, CD4+FOXP3+ T cells had a close interaction with CD8+ T cells rather than tumor cells. High densities of CD4+FOXP3+ T cells and CD8+ T cells (High-High) independently predicted prolonged patient survival. Furthermore, the interferon-gamma (IFN-γ) gene signature and PDL1 expression were up-regulated in this group. Importantly, a subgroup of genomically stable (GS) tumors and tumors with chromosomal instability (CIN) within this High-High group also had excellent survival. The High-High GS/CIN tumors were coupled with increased frequencies of Tbet+CD4+ T cells and central memory CD4+ T cells in the peripheral blood. CONCLUSION: These novel findings identify the combination of CD8+ T cells and FOXP3+CD4+ T cells as a significant prognostic marker for GC patients, which also could potentially be targeted and applied in the combination therapy with immune checkpoint blockades in precision medicine.

Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry.

Tumor-associated macrophages (TAMs), one of the most abundant immune components in gastric cancer (GC), are difficult to characterize due to their heterogeneity. Multiple approaches have been used to elucidate the issue, however, due to the tissue-destructive nature of most of these methods, the spatial distribution of TAMs in situ remains unclear. Here we probe the relationship between tumor context and TAM heterogeneity by multiplex immunohistochemistry of 56 human GC cases. Using distinct expression marker profiles on TAMs, we report seven predominant populations distributed between tumor and non-tumor tissue. TAM population-associated gene signatures reflect their heterogeneity and polarization in situ. Increased density of CD163+ (CD206-) TAMs with concurrent high CD68 expression is associated with upregulated immune-signaling and improved patient survival by univariate, but not multivariate analysis. CD68-only and CD206+ TAMs are correlated with high PDL1 expression.

Down-regulation of a pro-apoptotic pathway regulated by PCAF/ADA3 in early stage gastric cancer.

The loss of p300/CBP-associated protein (PCAF) expression is associated with poor clinical outcome in gastric cancer, and a potential bio-marker for invasive and aggressive tumors. However, the mechanism linking loss of PCAF to the onset of gastric cancer has not been identified. Given that PCAF and its binding partner transcriptional adaptor protein 3 (ADA3) were recently shown to regulate the intrinsic (mitochondrial) pathway to apoptosis via epigenetic regulation of phosphofurin acidic cluster sorting proteins 1 and 2 (PACS1, PACS2), we analyzed PCAF, ADA3, and PACS1/2 expression in 99 patient-matched surgical samples ranging from normal gastric mucosa, through pre-malignant chronic gastritis and intestinal metaplasia to stage I-III invasive cancers. PCAF mRNA levels were not reduced in either pre-malignant state but were significantly down-regulated in all stages of gastric cancer, commencing at AJCC stage I (p < 0.05), thus linking reduced PCAF expression with early malignant change. Furthermore, patients with combined reduction of PCAF and PACS1 had significantly poorer overall survival (p = 0.0257), confirmed in an independent dataset of 359 patients (p = 5.8 × 10e-6). At the protein level, PCAF, ADA3, and PACS1 expression were all significantly down-regulated in intestinal-type gastric cancer, and correlated with reduced progression free survival. We conclude that a pro-apoptotic mechanism centered on the intrinsic (mitochondrial) pathway and regulated by PCAF/ADA3 can influence the progression from premalignant to malignant change, and thus act as a tumor suppression mechanism in gastric cancer.

An orthotopic mouse model of gastric cancer invasion and metastasis.

Gastric cancer is a leading cause of cancer death worldwide, with advanced stage being correlated to the level of tumour invasion and metastasis. Current research is heavily focused on the identification and development of efficacious therapeutics targeting these fundamental hallmarks of cancer, however there are currently no animal models that mimic the invasive phenotypes observed in humans. To address this we have developed an orthotopic mouse model whereby gastric cancer cell lines are tagged with luciferase and injected into the subserosal layer of the stomach. This allows for the monitoring of primary tumour growth and metastasis in real-time as well as quantitation of the degree of tumour invasion through the stomach wall by immunohistochemistry. We have three models based on the degree of invasion and metastasis that are cell line specific: The AGS cells develop into invasive tumours by 4-weeks with no evidence of metastases, MKN45 cells are moderately metastatic with minimal invasion till week 2 and MKN28 cells are highly metastatic and fully invasive by week 1. These models have utility as a tool for testing the efficacy of anti-tumour, anti-invasive and anti-metastatic therapies in the setting of gastric cancer, which currently has poor treatment options.

Early relapses after adjuvant chemotherapy suggests primary chemoresistance in diffuse gastric cancer.

BACKGROUND: Survival from gastric cancer remains poor, particularly in Western populations. Previous pre-clinical and subgroup analyses of clinical trials have suggested differing benefits from fluoropyrimidine-based chemotherapeutics for diffuse and intestinal gastric cancer. This analysis examines patterns of relapse with and without adjuvant chemotherapy after curative resection for gastric cancer in these subtypes to explore the Lauren classification as a predictive marker of benefit for fluoropyrimidine-based adjuvant chemotherapy. PATIENTS AND METHODS: Gastric cancer patients enrolled in an ongoing tissue banking study were analysed, 164 patients who would currently be considered for adjuvant therapy after curative resection were included in the analysis. Patients who did and did not receive adjuvant chemotherapy were compared. The primary end point was relapse free survival. RESULTS: Approximately 50% of patients received adjuvant chemotherapy, the majority receiving a fluoropyrimidine-based regimen. The comparison of Kaplan-Meier curves for patients who did and did not receive adjuvant chemotherapy are different between patients with intestinal and diffuse gastric cancer, and suggest that there may be a benefit in intestinal gastric cancer. The hazard ratio for adjuvant chemotherapy for intestinal gastric cancer was 0.56, (95% CI 0.27-1.17), suggesting a trend towards benefit that was lacking in diffuse gastric cancer patients (1.26, 95% CI 0.70-2.38). The patterns of relapse after adjuvant chemotherapy also differed between diffuse and intestinal gastric cancer. More than 50% of diffuse gastric cancer patients who received adjuvant chemotherapy relapsed within 12 months of surgery despite similar surgical parameters. CONCLUSIONS: Lauren classification is prognostic in gastric cancer. This analysis adds further evidence that it may also be predictive of benefit for fluoropyrimidine-based chemotherapeutics, with lower chemosensitivity seen in diffuse gastric cancer. Treating diffuse and intestinal gastric cancer as separate entities, with identification of efficacious treatments for diffuse gastric cancer will help in improving outcomes from gastric cancer.

Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis.

There is currently a paucity of preclinical models available to study the metastatic process in esophageal cancer. Here we report FLO-1, and its isogenic derivative FLO-1LM, as two spontaneously metastatic cell line models of human esophageal adenocarcinoma. We show that FLO-1 has undergone epithelial-mesenchymal transition and metastasizes following subcutaneous injection in mice. FLO-1LM, derived from a FLO-1 liver metastasis, has markedly enhanced proliferative, clonogenic, anti-apoptotic, invasive, immune-tolerant and metastatic potential. Genome-wide RNAseq profiling revealed a significant enrichment of metastasis-related pathways in FLO-1LM cells. Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1. Consistent with this, repression of E-cadherin expression in FLO-1 cells resulted in increased metastatic activity. Importantly, reduced E-cadherin expression is commonly reported in esophageal adenocarcinoma and independently predicts poor patient survival. Collectively, these findings highlight the biological importance of E-cadherin activity in the pathogenesis of metastatic esophageal adenocarcinoma and validate the utility of FLO-1 parental and FLO-1LM cells as preclinical models of metastasis in this disease.

Immunological battlefield in gastric cancer and role of immunotherapies.

Like the wars predating the First World War where human foot soldiers were deemed tools in the battlefield against an enemy, so too are the host immune cells of a patient battling a malignant gastric cancer. Indeed, the tumour microenvironment resembles a battlefield, where the patient's immune cells are the defence against invading tumour cells. However, the relationship between different immune components of the host response to cancer is more complex than an "us against them" model. Components of the immune system inadvertently work against the interests of the host and become pro-tumourigenic while other components soldier on against the common enemy - the tumour cell.

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.

Predictors of outcome after surgery for gastric cancer in a Western cohort.

BACKGROUND: Gastric cancer (GC) is a common cause of cancer mortality. There are well-documented prognostic factors for GC but these have not been rigorously examined in an Australian context. This study examines the clinical, surgical and histopathological variables associated with survival in a GC cohort from a predominantly Caucasian-based population. METHODS: A multi-centre cohort of patients undergoing curative resection for GC enrolled in an ongoing tissue bank study from 1999 to 2009 was retrospectively analysed. Prospectively collected demographic, surgical and pathological variables were available for this cohort. The primary endpoints investigated were cancer-specific survival and recurrence-free survival using multivariate Cox proportional hazard modelling. RESULTS: Five-year cancer-specific survival was 45.9%, 5-year relapse-free survival was 44.7% and 30-day mortality was 2.2%. Variables showing significance on multivariate analysis for cancer-specific and relapse-free survival were AJCC stage, Lauren classification and age at surgery. CONCLUSION: This study demonstrates that the prognostic variables for a predominantly Caucasian GC population are congruent with published prognostic features. These findings emphasize the importance of the pathological review in allocating prognosis in GC.

Role of p53 in the progression of gastric cancer.

Intestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer (GC) but is poorly described in terms of molecular changes. Here, we explored the role of TP53, a commonly mutated gene in GC, to determine if p53 protein expression and/or the presence of somatic mutations in TP53 can be used as a predictive marker for patients at risk of progressing to GC from IM. Immunohistochemistry and high resolution melting were used to determine p53 protein expression and TP53 mutation status respectively in normal gastric mucosa, IM without concurrent GC (IM-GC), IM with concurrent GC (IM+GC) and GC. This comparative study revealed an incremental increase in p53 expression levels with progression of disease from normal mucosa, via an IM intermediate to GC. TP53 mutations however, were not detected in IM but occurred frequently in GC. Further, we identified increased protein expression of Mdm2/x, both powerful regulators of p53, in 100% of the IM+GC cohort with these samples also exhibiting high levels of wild-type p53 protein. Our data suggests that TP53 mutations occur late in gastric carcinogenesis contributing to the final transition to cancer. We also demonstrated involvement of Mdmx in GC.

A signature predicting poor prognosis in gastric and ovarian cancer represents a coordinated macrophage and stromal response.

PURPOSE: Gene-expression profiling has revolutionized the way we think about cancer and confers the ability to observe the synchronous expression of thousands of genes. The use of putative genome-level expression profiles has allowed biologists to observe the complex interactions of genes that constitute recognized biologic pathways. We used gastric and ovarian datasets to identify gene-expression signatures and determine any functional significance. EXPERIMENTAL DESIGN: Microarray data of 94-tumor and 45-benign samples derived from patients with gastric cancer were interrogated using Hierarchical Ordered Partitioning and Collapsing Hybrid analysis identifying clusters of coexpressed genes. Clusters were further characterized with respect to biologic significance, gene ontology, and ability to discriminate between normal and tumor tissue. Tumor tissues were separated into epithelial and stromal compartments and immunohistochemical analysis performed to further elucidate specific cell lineages expressing genes contained in the signature. RESULTS: We identified a "stromal-response" expression signature, highly enriched for inflammatory, extracellular matrix, cytokine, and growth factor proteins. The majority of genes in the signature are expressed in the tumor-associated stroma but were absent in associated premalignant conditions. In gastric cancer, this module almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as a highly tumor-specific gene-expression signature. CONCLUSIONS: We show that these genes are consistently coexpressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. In addition, we show that this signature can be a surrogate marker for M2 macrophage activity and has significant prognostic implications in gastric and ovarian high-grade serous cancer.

Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically.

Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer "hallmarks" through downstream activation of the gp130/STAT3 signaling pathway. However, we show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in these models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors. Our results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers.

Lifespan extension by dietary restriction is not linked to protection against somatic DNA damage in Drosophila melanogaster.

Dietary restriction (DR) has been shown to robustly extend lifespan in multiple species tested so far. The pro-longevity effect of DR is often ascribed to an increase in cellular defense against somatic damage, most notably damage by reactive oxygen species (ROS), considered a major cause of aging. Especially irreversible damage to DNA, the carrier of genetic information, is considered a critical causal factor in aging. Using a recently developed transgenic Drosophila melanogaster model system harboring a lacZ-plasmid construct that can be recovered in E. coli, spontaneous DNA mutation frequency in flies under DR and ad libitum conditions are measured. Three different DR conditions, imposed by manipulating levels of different types of yeast sources, were tested in females and males of two lacZ reporter gene lines. Feeding with the ROS producer paraquat at 1 mM resulted in a rapid accumulation of somatic mutations, indicating that the frequency of mutations at the lacZ locus is a reliable marker for increased oxidative stress. However, none of the DR conditions altered the accumulation of spontaneous mutations with age. These results suggest that the beneficial effects of DR are unlikely to be linked to protection against oxidative somatic DNA damage.

Intestinal metaplasia: a premalignant lesion involved in gastric carcinogenesis.

Despite a plateau in incidence, gastric cancer remains a significant problem globally. The majority of gastric cancer is associated with histologically recognizable premalignant stages as first described by Pelayo Correa in the mid-1970s. The mortality from gastric cancer remains high especially in Western countries where, arguably, the index of suspicion of gastric cancer in patients presenting with upper abdominal symptoms is lower than in high prevalence countries. What is the evidence that intestinal metaplasia (IM) is a premalignant condition? What should the clinician know about IM and the relative risks of progression to gastric cancer? Finally, what are the current and future strategies that may help stratify patients into high risk and low risk for the development of gastric cancer? This review focuses on gastric IM and outlines some of the literature that discusses it as a premalignant condition. It also reviews the issue of surveillance of patients with IM in order to attempt to reduce the significant mortality of gastric cancer by detection of earlier stages of disease which are eminently treatable.

Ku80 deletion suppresses spontaneous tumors and induces a p53-mediated DNA damage response.

Ku80 facilitates DNA repair and therefore should suppress cancer. However, ku80(-/-) mice exhibit reduced cancer, although they age prematurely and have a shortened life span. We tested the hypothesis that Ku80 deletion suppresses cancer by enhancing cellular tumor-suppressive responses to inefficiently repaired DNA damage. In support of this hypothesis, Ku80 deletion ameliorated tumor burden in APC(MIN) mice and increased a p53-mediated DNA damage response, DNA lesions, and chromosomal rearrangements. Thus, contrary to its assumed role as a caretaker tumor suppressor, Ku80 facilitates tumor growth most likely by dampening baseline cellular DNA damage responses.