Inflammation and Ovarian Cancer

Macci, Antonio; Madeddu, Clelia

doi:10.5772/26688

Cited by 41 publications

(62 citation statements)

References 33 publications

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“…However, it must be recognized that the presence of Interleukin (IL)−6, which is associated with M1 TAM polarization 2 , would modify this situation because it is recognized that IL-6 has immunosuppressive actions (such as inflammation) in the tumor microenvironment. The fact that IL-6 exerts a bivalent action is one of the most controversial aspects of the role of the immune system in the tumor microenvironment of advanced ovarian cancer, as demonstrated in our previous papers 25,26 . This aspect should, however, be better studied because while the role of IL-6 in the modification of iron metabolism through hepcidin is well established, its role in immune system modulation is different in the various phases of cancer progression 27 .…”

Section: Discussionmentioning

confidence: 92%

Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients

Macciò

Gramignano²,

Cherchi

et al. 2020

Sci Rep

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111

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The identification of prognostic and predictive markers is crucial for choosing the most appropriate management method for ovarian cancer patients. We aimed to assess the prognostic role of tumorassociated macrophage (TAM) polarization in advanced ovarian cancer patients. We carried out a prospective observational study that included 140 consecutive patients with advanced-stage highgrade serous ovarian cancer as well as patients with other histotypes of ovarian cancer and patients with ovarian metastasis from other sites between June 2013 and December 2018. Patients were enrolled at the time of laparoscopic surgery before receiving any antineoplastic treatment. We found that patients with high-grade serous papillary ovarian cancers had a prevalence of M1 TAMs, a higher M1/M2 ratio, and a longer overall survival (OS) and progression-free survival (PFS) than other patients. Regression analysis confirmed that there was a significant positive association between the M1/M2 ratio and an improved OS, PFS and platinum-free interval (PFI), both in the entire population and in patients stratified according to tumor type and initial surgery. Kaplan-Meier analysis was performed after the patients were divided into 2 groups according to the median M1/M2 ratio and revealed that patients with a high M1/M2 ratio had a higher OS, PFS and PFI than those with a low M1/M2 ratio. In conclusion, the prognostic and predictive role of TAM polarization in the tumor microenvironment could be of great clinical relevance and may allow the early identification of patients who are likely to respond to therapy. Further studies in a larger prospective sample are warranted.www.nature.com/scientificreports www.nature.com/scientificreports/ linear relationship (β coefficient = 0.504, 95% CI 0.493-10.334, p = 0.033) was found between the platinum-free interval and M1/M2 ratio (Fig. 2).The median value for the M1/M2 ratio was 1.4. Then, we analyzed the difference in OS and PFS by Kaplan-Meier curve analysis and log-rank analysis between patients with an M1/M2 ratio ≥ 1.4 and those with an M1/M2 ratio < 1.4. We found that patients with an M1/M2 ratio ≥ 1.4 had a significantly longer OS (34 months versus 18 months, HR 2.7483, 95% CI: 1.1667-6.4736; p = 0.0207), PFS (24 months versus 9 months, HR 2.1285, 95% CI: 1.0461-4.3309; p = 0.0371) and PFI (12 months versus 6 months, HR 3.3959, 95% CI 1.2471-9.2469; p = 0.0168) ( Fig. 3). Scientific RepoRtS |(2020) 10:6096 | https://doi.

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Section: Discussionmentioning

confidence: 92%

Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients

Macciò

Gramignano²,

Cherchi

et al. 2020

Sci Rep

Self Cite

111

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“…Co‐culturing macrophages with ovarian cancer cell lines can significantly increase the invasiveness of the tumour cells. Recent studies have demonstrated the role of NF‐κB in malignant progression 36,37 …”

Section: Discussionmentioning

confidence: 99%

RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF‐κB pathway

Jiang

Wan

Gong

et al. 2020

J Cellular Molecular Medi

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Methylation is the main form of RNA modification. N6‐methyladenine (m6A) regulates the splicing and translation of mRNA. Alk B homologue 5 (ALKBH5) participates in the biological regulation of various cancers. However, its role in ovarian carcinogenesis has not been unveiled. In the present study, ALKBH5 showed higher expression in ovarian cancer tissue than in normal ovarian tissue, but lower expression in ovarian cancer cell lines than in normal ovarian cell lines. Interestingly, Toll‐like receptor (TLR4), a molecular functioning in tumour microenvironment (TME), demonstrated the same expression trend. To investigate the effect of abnormal TME on ovarian carcinogenesis, we established an in vitro model in which macrophages and ovarian cancer cells were co‐cultured. In the ovarian cancer cells co‐cultured with M2 macrophages, the expression of ALKBH5 and TLR4 increased. We also verified that TLR4 up‐regulated ALKBH5 expression via activating NF‐κB pathway. Depending on transcriptome sequencing, m6A‐Seq and m6A MeRIP, we found that NANOG served as a target in ALKBH5‐mediated m6A modification. NANOG expression increased after mRNA demethylation, consequently enhancing the aggressiveness of ovarian cancer cells. In conclusion, highly expressed TLR4 activated NF‐κB pathway, up‐regulated ALKBH5 expression and increased m6A level and NANOG expression, all contributing to ovarian carcinogenesis. Our study revealed the role of m6A in ovarian carcinogenesis, providing a clue for inventing new target therapy.

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“…Cachexia is primarily responsible for body and muscle weight loss and correlates with tumour burden, increased pro-inflammatory cytokine levels, fatigue, and reduced response to chemo-therapy and radiotherapy. [17][18][19] Patients presenting with advanced stage OC often show large tumour and ascites burden that, in turn, results into severe malnourishment because of decreased oral intake and compromised bowel functions. As a consequence, malnutrition and weight loss are frequently diagnosed and together contribute to substantial impairment of anti-cancer treatments and poorer prognosis.…”

Section: Introductionmentioning

confidence: 99%

Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia

Barreto

Kitase

et al. 2018

J cachexia sarcopenia muscle

124

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BackgroundCachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under‐studied in OC due to a limited number of pre‐clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC.MethodsNod SCID gamma mice (n = 6–10) were injected intraperitoneally with 1 × 107 ES‐2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour‐derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL‐6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections.ResultsIn about 2 weeks, ES‐2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES‐2 tumours caused severe cachexia with marked loss of body weight (–12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour‐bearing mice (approximately –35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross‐sectional area (–34%, P < 0.01) and muscle weakness (–50%, P < 0.001). Body composition assessment by dual‐energy X‐ray absorptiometry revealed decreased bone mineral density (–8%, P < 0.01) and bone mineral content (–19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro‐CT imaging of bone morphometry. In the ES‐2 mouse model, cachexia was also associated with high tumour‐derived IL‐6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho‐STAT3 (+274%, P < 0.001), reduced phospho‐AKT (–44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES‐2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (–16%, P < 0.001), consistent with elevated phospho‐STAT3 (+1.4‐fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL‐6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size.ConclusionsOur results suggest that the development of ES‐2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL‐6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.

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Inflammation and Ovarian Cancer

Cited by 41 publications

References 33 publications

Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients

Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients

RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF‐κB pathway

Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia

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