Can killers be saviors
TL;DR: This is an attempt to take an account of malicious ‘lupus autoantibodies’ and their role in neutralizing cancerous cells which may help in enhancing the survival rate of cancer patients, hence, killers can be saviors.
Abstract: Autoimmunity and cancer have a multifarious epidemiology. Often, it is because of an impaired genome, culminating in functional aberrations in the human system. Systemic lupus erythematosus (SLE) is a heterogeneous complex disease which ensues due to the failure of the immune system to distinguish between self and non-self antigens, thus producing autoantibodies against DNA, RNA and proteins. Cancer, the other side of the same coin, results from an excessive proliferation of cells that evade immune regulation as a result of incompetent defense by T-cells, B-cells and macrophages. Recent findings have indicated that lupus autoantibodies could be used as an effective weapon to kill cancerous cells. This is an attempt to take an account of malicious 'lupus autoantibodies' and their role in neutralizing cancerous cells which may help in enhancing the survival rate of cancer patients, hence, killers can be saviors.
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TL;DR: Larger studies are needed to investigate which particular antibody/ies against/to specific NA is responsible for the association between nucleolar ANA and cancer, but anti-Scl70 and anti-RNAP-III, which is frequently associated with the presence of anti- RNAP-I, are good candidates to explain this association.
Abstract: Background: Different antinuclear antibody (ANA) patterns have been associated with the presence of cancer, while other are typically seen in autoimmune diseases. This study aims to investigate the association between ANA and cancer, focusing on patients with ANA with a nucleolar indirect immunofluorescence (IIF) pattern. Materials and Methods: ANA patterns and positivity of antibodies against nuclear antigens (NA), in particular those responsible for a nucleolar ANA pattern and/or associated with systemic sclerosis (CENP-A/B, fibrillarin, Ku, NOR-90, PM/Scl-100, PM/Scl-75, RNAP-III, Scl-70, Ro52/TRIM21, and Th/To) were analyzed and correlated to an internal database of patients with cancer. Results: The study included 15,728 patients who had an ANA analysis, 386 patients who had immunodot analysis for antibody/ies against/to specific NA and 15,701 patients diagnosed with cancer. The presence of ANA with a nucleolar pattern showed an increased relative risk (RR 1.5, 95%CI 1.03-2.3) for an associated cancer. Anti-Scl70 and anti-RNAP-III were associated with cancer in 15 and 14%, respectively. The presence of ANA with a homogeneous & speckled (HS) pattern was significantly associated with the absence of cancer (p < 0.01). Patients with a HS pattern were found to have a lower relative risk (RR 0.7, 95%CI 0.5-0.9) of having cancer compared to those with other patterns. Conclusions: Larger studies are needed to investigate which particular antibody/ies against/to specific NA is responsible for the association between nucleolar ANA and cancer, but anti-Scl70 and anti-RNAP-III, which is frequently associated with the presence of anti-RNAP-I, are good candidates to explain this association. Patients with a nucleolar pattern might be considered for cancer screening, in particular if they have anti-Scl70 and anti-RNAP-III antibodies.
12 citations
TL;DR: It is indicated that SLE patients with cancers might have a lower disease activity at the time of cancer diagnosis, and the administration of HCQ was significantly lower in Sle patients suffering cancers relative to the cancer-free matched control group.
Abstract: Systemic lupus erythematosus (SLE) is associated with increased risk of cancer and the mechanism remains unclear Here, we examined the level of auto-antibodies and disease activity index scores in SLE patients with cancers and analyzed whether medications for SLE management might contribute to the higher cancer risk in SLE patients In this retrospective study, we carried out a nested case-control study in a large cohort of SLE patients We screened 5858 SLE patients to identify the newly diagnosed and yet to be treated cancers The following clinical features were evaluated: auto-antibodies levels, SLE disease activity index scores, and previous medication used for SLE management Systemic glucocorticoid, cyclophosphamide, hydroxychloroquine (HCQ), methotrexate, and azathioprine were considered the main medication indices Our analyses identified 51 SLE patients who also had cancer and 204 matched control patients who had SLE but not cancer Of the 51 SLE patients, thyroid cancer (14/51, 2745%), cervical cancer (10/51, 1961%), and lung cancer (7/51, 1373%) were the most common types Our analyses did not reveal any significant differences in the levels of auto-antibodies in SLE patients with cancers relative to the control group Further, we observed that disease activity was significantly lower in SLE patients with cancers relative to the matched control SLE group There was no statistically significant association between the cancer risk and the use of systemic glucocorticoid, cyclophosphamide, methotrexate, or azathioprine Importantly, the administration of HCQ was significantly lower in SLE patients suffering cancers relative to the cancer-free matched control group Our analyses indicate that SLE patients with cancers might have a lower disease activity at the time of cancer diagnosis HCQ was negatively associated with cancer risk in SLE patients These findings highlight a potential and novel prevention strategy for SLE
9 citations
TL;DR: Wang et al. as discussed by the authors investigated the association between ANA patterns and the outcome of leukemia in a retrospective cohort and found that patients with a nucleolar pattern had shorter survival than those with a non-nucleolar pattern or without ANA.
Abstract: Objective: Antinuclear antibodies (ANAs) have been reported to be associated with cancers. However, the role of different ANA patterns in cancers is poorly understood, especially in leukemia. This study aimed to investigate the association between ANA patterns and the outcome of leukemia in a retrospective cohort. Methods: A total of 429 adult patients initially diagnosed with leukemia at Henan Provincial People’s Hospital from January 2014 to December 2018 were included in this study, including information on patients without positive ANAs at the time of initial diagnosis, preexisting autoimmune diseases, infectious diseases, et al. The data were retrieved up to December 2020. The final sample included 196 adult patients. The risk of death outcome according to ANA patterns was estimated using multivariable Cox proportional hazards models and the overall survival for ANA patterns was analyzed using Kaplan–Meier curve. Results: ANAs with a nucleolar pattern versus negative ANA were associated with a two-fold increased risk of death outcome in leukemia, independent of sex, age, leukemia immunophenotype, cytogenetic abnormality, treatment and blood transfusion. Further analysis revealed that the association was more significant in elder patients (≥ 60 years) and patients treated with tyrosine kinase inhibitor or chemotherapy (P for interaction = 0.042 and 0.010). Notably, the patients with a nucleolar pattern had shorter survival than the patients with a non-nucleolar pattern or without ANA (p < 0.001), Conclusion: ANAs with a nucleolar pattern are a significant predictor of poor prognosis, providing clues for prognostic assessment in patients with leukemia.
5 citations
TL;DR: In this paper , the authors compared survival in patients with lung cancer with and without auto-immunity and found that patients with autoimmune disease had higher overall survival (OS) and reduced cancer-specific mortality (CSM).
Abstract: IntroductionAutoimmune disease has both a predisposing and a protective effect toward malignancy. Though studies have investigated the risk of malignancy in patients with autoimmune disease, there is limited research on how autoimmunity affects survival.MethodsThis study compared survival in patients with lung cancer with and without autoimmune disease. Patients with lung cancer were culled from the Surveillance, Epidemiology, and End Results Medicare databases (2007–2014), and autoimmune diseases were identified using diagnosis codes.ResultsThe overall prevalence of investigated autoimmune diseases among the 112,445 patients was 22.7%. Overall survival (OS) (p < 0.0001) was longer and cancer-specific mortality (CSM) (p < 0.0001) reduced among patients with autoimmune disease. Median OS was 5 months higher. Improved OS and CSM were also apparent in disease stages 1, 3, and 4 in the NSCLC and SCLC subgroups (p < 0.0001) and across most specific autoimmune diseases. After adjusting for the effects of age, sex, race, disease stage, and chronic kidney disease, autoimmune disease was still predictive of higher OS (hazard ratio = 1.23, 95% confidence interval: 1.21–1.25, p < 0.0001) and reduced CSM (hazard ratio = 1.16, 95% confidence interval: 1.14–1.18, p < 0.0001).ConclusionsThe prevalence of rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematous was highly enriched compared with the general population. The improvement in OS and CSM was larger in NSCLC than in SCLC, suggesting a larger role for the immune system in NSCLC. Alternate explanations for the improved survival include lead time bias, better access to health care, and a survival or autoimmunity-inducing genetic factor.
1 citations
TL;DR: High dosage of CTX and disease-related factors (low SLEDAI-2K, less mucocutaneous and hematologic involvement) were related factors for cancer occurrence after SLE, while no survival difference was observed.
Abstract: OBJECTIVES
To explore the survival and risk factors for cancer occurrence after systemic lupus erythematosus (SLE-CA).
METHODS
Patients with cancer diagnosed after SLE in Peking Union Medical College Hospital between January 2006 and September 2017 were recruited and followed. Data regarding medication-related and disease-related factors and survival were collected and compared with matched controls. Logistic regressions were applied to identify risk factors. Kaplan-Meier method with a log-rank test was performed to evaluate survival.
RESULTS
Forty-five SLE-CA patients and 128 controls were included, with the most common cancer site of the female genital system. SLE-CA patients were exposed to a higher cumulative dosage of cyclophosphamide (CTX), with less mucocutaneous and hematologic involvement and higher anti-dsDNA positivity. At the time of cancer diagnosis, SLE-CA patients had lower SLEDAI-2K, tend to achieve DORIS remission and minimal disease activity, but had higher SLICC/ACR Damage Index. Multivariable analysis identified high dosage of CTX (odds ratio (OR) 1.027, 95% confidence interval (CI) 1.008-1.046; p = 0.005) and low SLEDAI-2K at cancer diagnosis (OR 0.756, 95%CI 0.579-0.986; p = 0.039) as risk factors. Mucocutaneous (OR 0.330, 95%CI 0.110-0.991; p = 0.048) and hematologic involvement (OR 0.304, 95%CI 0.103-0.902; p = 0.032) were negatively associated with cancer occurrence after SLE. The 5- and 10-year survival rates in SLE-CA patients were 95.2% and 92.1%, respectively. No significant difference of survival was observed between SLE-CA patients and controls (p = 0.177).
CONCLUSION
High dosage of CTX and disease-related factors (low SLEDAI-2K, less mucocutaneous and hematologic involvement) were related factors for cancer occurrence after SLE, while no survival difference was observed.
References
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
51,099 citations
7,570 citations
TL;DR: This work reports monoallelic frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls, and demonstrates that two mutant TREx1 alleles alter subcellular targeting.
Abstract: TREX1 acts in concert with the SET complex in granzyme A–mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutieres syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 × 10−7). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.
604 citations
TL;DR: Cancer cells use "oxidative stress" in adjacent fibroblasts as an "engine" to fuel their own survival via the stromal production of nutrients, and to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability.
Abstract: Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg Effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use "oxidative stress" in adjacent fibroblasts (i) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"--spread from cell-to-cell like a virus--creating an "oncogenic/mutagenic" field promoting widespread DNA damage.
433 citations
TL;DR: Analysis of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses in patients with scleroderma and provided support for the idea that acquired immunity helps to control naturally occurring cancers.
Abstract: Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, we hypothesized that the “foreign” antigens in this autoimmune disease are encoded by somatically mutated genes in the patients’ incipient cancers. Studying cancers from scleroderma patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma and provide support for the idea that acquired immunity helps to control naturally occurring cancers.
361 citations