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Acute-phase proteins (APPs) are associated with a variety of disorders such as infection, inflammatory diseases, and cancers. The signature profile of APPs in breast cancer (BC) is poorly understood. Here, we identified serum amyloid A (SAA) for proinflammatory predisposition in BC through the signature profiles of APPs, interleukin (IL) and tumor necrosis factor (TNF) superfamily using publicly available datasets of tumor samples and cell lines. Triple-negative breast cancer (TNBC) subtype highly expressed SAA1/2 compared to HER2, luminal A (LA) and luminal B (LB) subtypes. IL1A, IL1B, IL8/CXCL8, IL32 and IL27RA in IL superfamily and CD70, TNFSF9 and TNFRSF21 in TNF superfamily were highly expressed in TNBC compared to other subtypes. SAA is restrictedly regulated by nuclear factor (NF)-κB and IL-1β, an NF-κB activator highly expressed in TNBC, increased the promoter activity of SAA1 in human TNBC MDA-MB231 cells. Interestingly, two κB-sites contained in SAA1 promoter were involved, and the proximal region (−96/−87) was more critical than the distal site (−288/−279) in regulating IL-1β-induced SAA1. Among the SAA receptors, TLR1 and TLR2 were highly expressed in TNBC. Cu-CPT22, TLR1/2 antagonist, abrogated IL-1β-induced SAA1 promoter activity. In addition, SAA1 induced IL8/CXCL8 promoter activity, which was partially reduced by Cu-CPT22. Notably, SAA1/2, TLR2 and IL8/CXCL8 were associated with a poor overall survival in mesenchymal-like TNBC. Taken together, IL-1-induced SAA via NF-κB-mediated signaling could potentiate an inflammatory burden, leading to cancer progression and high mortality in TNBC patients.

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle genesilencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: this study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC., NHMRC Project Grant; Avner Innovation Grant; NHMRC CDF-I; NHMRC Ideas Grant ; Cancer-Institute NSW ECF/CDFs ; Cancer Institute NSW Innovation Grant; Cancer Institute NSW The Professor Rob Sutherland AO Make a Difference Award; Cancer Australia/Cancer Council; Cancer Australia/Kids Cancer Project; Cure Cancer Australia; Tour de Cure PhD Support Scholarship; Tour de Cure Established Research Grant; Tour de Cure Pioneering Research Grant; UNSW Interlude Grant Scheme; Cancer Research UK Core Funding and Grand Challenge Grants; NHMRC CDF-II; NHMRC Senior Research Fellowship; Suttons, Cancer Council NSW; Avner Grant from PanKind; Australian Pancreatic Cancer Foundation; Translational Cancer Research Network and Australian Postgraduate Award Scholarships; Australian Government Research Training Program Scholarship; UNSW Sydney Scientia PhD Scholarship; Pancreatic Cancer UK Future Leaders Academy; Len Ainsworth Pancreatic Cancer Fellowship

One-fifth of cancer deaths are associated with obesity. Because the molecular mechanisms by which obesity affects the progression of ovarian cancer (OC) are poorly understood, we investigated if obesity could promote the progression of OC cells using the postmenopausal ob/ob mouse model and peritoneal dissemination of mouse ID8 OC cells. Compared to lean mice, obese mice had earlier OC occurrence, greater metastasis throughout the peritoneal cavity, a trend toward shorter survival, and higher circulating glucose and proinflammatory chemokine CXCL1 levels. Ascites in obese mice had higher levels of macrophages (Mφ) and chemokines including CCL2, CXCL12, CXCL13, G-CSF and M-CSF. Omental tumor tissues in obese mice had more adipocytes than lean mice. Our data suggest that obesity may accelerate the peritoneal dissemination of OC through higher production of pro-inflammatory chemokines and Mφ recruitment.

Pancreatic cancer is predicted to be the second leading cause of cancer-related death by 2025. The best chemotherapy only extends survival by an average of 18 weeks. The extensive fibrotic stroma surrounding the tumor curbs therapeutic options as chemotherapy drugs cannot freely penetrate the tumor. RNA interference (RNAi) has emerged as a promising approach to revolutionize cancer treatment. Small interfering RNA (siRNA) can be designed to inhibit the expression of any gene which is important given the high degree of genetic heterogeneity present in pancreatic tumors. Despite the potential of siRNA therapies, there are hurdles limiting their clinical application such as poor transport across biological barriers, limited cellular uptake, degradation, and rapid clearance. Nanotechnology can address these challenges. In fact, the past few decades have seen the conceptualization, design, pre-clinical testing and recent clinical approval of a RNAi nanodrug to treat disease. In this review, we comment on the current state of play of clinical trials evaluating siRNA nanodrugs and review pre-clinical studies investigating the efficacy of siRNA therapeutics in pancreatic cancer. We assess the physiological barriers unique to pancreatic cancer that need to be considered when designing and testing new nanomedicines for this disease.

ObjectivesEven though Philippines is widely known as exporters of health workers in the world, the Occidental Mindoro province suffers from a lack of health workers compared with the total population of each municipality. The aim of this study was to observe, identify, and understand the persisting health status, knowledge, and practices among the three selected communities in Occidental Mindoro, Philippines.MethodsThe study applied a survey using basic questions with three key topics, with relevance to the health condition of the villagers, such as demographics (social capital and regional characteristics), lifestyle (healthy living, and healthy lifestyle and behavior), and status or position in the society (general demographics, and personal behavior and attitudes), with a random sample of 256 adult respondents.ResultsOnly about 54.3% rated themselves as fair/moderately healthy, and a total of 17.2% suffered from chronic diseases such as diabetes mellitus, cancers, chronic obstructive pulmonary disease, and cardiovascular disease, while 9% have been diagnosed with tuberculosis in the past 6 months. Respondents mostly have low income and low education.ConclusionThe majority of the respondents have only primary and secondary education, and a very low average income; these suggest that respondents were afflicted with poverty and low educational attainment. Respondents who are deprived of their rights to obtain a higher education also have a higher chance of having less knowledge on their well-being. Health programs do not guarantee a healthy individual and a healthy society, but a combination of health programs and socioeconomic support can help in creating a healthy community.

It is widely accepted that chronic inflammation contributes to the pathogenesis of obesity. Researchers have recently discovered that increased inflammatory cytokines and the infiltration and activation of macrophage cells in the adipose tissue are related to chronic obesity. This immunologic dysregulation has led to the development of the classical pro-inflammatory paradigm. However, since chronic inflammation associated with obesity is more than just the overproduction of pro-inflammatory cytokines, precise dissection requires beyond the classical pro-inflammatory cytokines. The purpose of this review is to summarize the immunological profiling of obesity for theragnostic convenience, focusing on the cytokine and adipokine network in obesity and the significance of the balance of Th1/Th2 immunity.

Triple-negative breast cancer (TNBC) is aggressive, leading to poorer outcomes. Chemokines have chemoattractive potential for cancer metastasis. We investigated the signature of chemokine network between TNBC and non-TNBC cells followed by underlining mechanisms on enhanced proinflammatory chemokines in TNBC. Analysis from microarray dataset revealed that basal-like BC subtype representing TNBC expressed dominantly proinflammatory chemokines, such as CXCL1 and 8, compared to non-TNBC. Chemokine PCR array confirmed the dominant proinflammatory chemokines in TNBC cells. As a driving factor for proinflammatory chemokines in TNBC cells, we checked expression profiles for epidermal growth factor receptor (EGFR) family and its downstream signaling. TNBC cells showed higher expression levels of EGFR and phosphorylated Akt compared to non-TNBC cells. In addition, EGF enhanced the proinflammatory chemokines in TNBC cells. Knockdown of Akt reduced the CXCL2 promoter activity, while overexpression of Akt enhanced the activity. MKK2206, an Akt inhibitor, abrogated the CXCL2 promoter activity, but targeting Erk using inhibitor and knockdown did not reduce the activity. As a driving factor for EGFR-mediated Akt activation in TNBC cells, we found transforming growth factor alpha (TGFα) among ligands of EGFR family. MK2206 decreased the TGFα promoter activity, while overexpression of Akt significantly increased the activity in TNBC cells. MK2206 abrogated TGFα protein released by TNBC cells. MK2206 downregulated CXCL2 mRNA, while TGFα upregulated the CXCL2 expression. Taken together, higher expression of proinflammatory chemokines in TNBC involves TGFα-EGFR-Akt axis, probably contributing to the inflammatory burden followed by promoted cancer progression and higher mortality in TNBC. Citation Format: Rosa Mistica Coles Ignacio, Carla Gibbs, Eunsook Lee, Deok-Soo Son. Involvement of TGFa-EGFR-Akt axis on enhanced proinflammatory chemokines in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5073.

Obesity has become a global epidemic and causes a chronic low-grade inflammation. This poses a large health burden because excess adiposity can lead to chronic diseases such as type 2 diabetes, cardiovascular disease and some cancers. Obese individuals get higher incidence, progression and mortality of cancers compared to lean ones. Particularly, breast cancer (BC) in women is closely associated with obesity. Despite an epidemiological link between obesity and low cancer survival rates, little is known about the molecular mechanisms by which obesity promotes BC progression. Obesity-derived chronic low-grade inflammation involves alteration of a chemokine network that may contribute to the cancer progression and metastasis. Herein, we proposed the novel concept that the chemokine network between obesity and BC builds an inflammatory burden via proinflammatory chemokines to promote cancer progression. We employed mesenchymal BC cell PY8119 and epithelial-like BC PY230 for triple negative BC (TNBC) cell model, and mouse 3T3-L1 preadipocyte and adipocyte conditioned media (CM) to mimic lean and obese conditions in vitro. We examined the profiles of chemokine signature of PY8119 and PY230 treated with preadipocytes and adipocytes CM using PCR array. Both preadipocytes and adipocytes CM-treated PY8119 and PY230 cells absent or low levels in chemokine receptors. On the other hand, the chemokines CCL2, 5, 7 and CXCL10 showed higher expression in both preadipocyte and adipocyte CM-treated PY8119. Interestingly, adipocyte CM-treated PY8119 cells dominantly expressed CXCL1-3 compared to preadipocyte CM-treated cells. In addition, CCL2, 5, 7, 20, and CXCL1, 5, 10 were highly expressed in both preadipocyte and adipocyte CM-treated PY230 cells. Moreover, CXCL2 and 3 were significantly induced in PY230 cells after treatment with adipocyte CM compared to preadipocyte CM. Taken together, the results indicate that dominant chemokines CXCL1-3 expressed in adipocyte CM-treated TNBC cells promote a pro-tumor inflammatory network. Hence, these proinflammatory microenvironment augmented by adipocytes might contribute to TNBC progression. Citation Format: Rosa Mistica Coles Ignacio, Hyeongjwa Choi, Carla Gibbs, Eunsook Lee, Samuel Adunyah, Deok-Soo Son. Involvement of proinflammatory chemokine network between adipocytes and triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 950. doi:10.1158/1538-7445.AM2017-950

Breast cancer (BC) is the most frequent tumor in women worldwide. Although its mortality has significantly decreased owing to advanced therapies, triple negative breast cancer (TNBC) is still difficult to treat because of lack of estrogen receptor, progesterone receptor and HER-2. TNBC accounts for 12-24% of total BC and contributes to the aggressiveness and poorer outcomes. The risk of BC increases significantly in obese women. Obesity is also associated with the worse clinical prognosis of BC. But the underlying mechanisms between obesity and BC, particularly TNBC, remain unclear. Therefore, we compare the molecular mechanisms by which human adipocyte conditioned media (CM) affect TNBC cells (BT549) and non-TNBC cells (MCF7A). Adipocyte CM had no effect on the proliferation of both TNBC and non-TNBC cells. However, adipocyte CM enhanced significantly migration in TNBC cells compared to non-TNBC cells. Next, we examined the signaling pathway by which adipocyte CM promote migration of TNBC cell. AKT and ERK were activated in both TNBC cells and non-TNBC cells. However, phospho-STAT3 was significantly increased in TNBC cells. Also, N-cadherin, a marker for epithelial to mesenchymal transition (EMT), was increased at the late time point in TNBC cells. Furthermore, CXCR7 was specifically increased in TNBC cells after treatment with adipocyte CM using a PCR array. CXCR7 is chemoattractive to CXCL12 which is highly expressed in the lung, the bone marrow, and the liver, common sites of BC metastasis. Taken together, the results indicate that adipocyte CM may promote metastasis of TNBC cells through the CXCL12-CXCR7 axis by activating STAT3. Citation Format: Hyeongjwa Choi, Rosa Mistica C. Ignacio, Carla R. Gibbs, Eunsook Lee, Samuel E. Adunyah, Deok-Soo Son. Involvement of CXCL12-CXCR7 axis in adipocyte-induced TNBC metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2933. doi:10.1158/1538-7445.AM2017-2933

Tumor necrosis factor-α (TNF) is well known to be involved in the immune system and ovarian inflammation. Ovarian cancer is an inflammation-related malignancy that lacks early screening strategies, resulting in late diagnosis followed by high mortality. Based on our previous data, TNF induced abundant serum amyloid A (SAA), an acute phase protein linked to inflammation, in ovarian granulosal cells. To date, the regulation and expression of SAA in ovarian cancer is not fully elucidated. Here, we investigated the relationship between TNF and SAA by comparing human normal ovarian tissues and serous ovarian tumors. We found that SAA1/2 was significantly expressed in tumor tissues, but no or trace expression levels in normal tissues. TNF was also significantly upregulated in ovarian tumor tissues compared to normal tissues. Moreover, TNF significantly increased SAA1/2 levels in human ovarian cancer cell lines, OVCAR-3 and SKOV-3, in a time-dependent manner. Since the SAA1 promoter contains two nuclear factor (NF)-κB sites, we examined whether TNF regulates SAA1 promoter activity. Deletion analysis revealed that the proximal NF-κB site (-95/-85) played a critical role in regulating TNF-induced SAA1 promoter activity. Within 2 h after intraperitoneal injection of lipopolysaccharide, a product known to stimulate release of TNF, SAA preferably localized to ovarian epithelial cells and the thecal-interstitial layers compared to granulosal cell layers. Based on Gene Expression Omnibus (GEO) database, SAA1/2 and TNF were dominantly expressed in advanced grade ovarian cancer. Taken together, the accumulation of SAA1/2 in ovarian cancer could be mediated by TNF-induced NF-κB activation.

Hydrogen water (HW) produced by electrolysis of water has characteristics of extremely low oxidation-reduction potential (ORP) value and high dissolved hydrogen (DH). It has been proved to have various beneficial effects including antioxidant and anti-inflammatory effects; however, HW effect on atopic dermatitis (AD), an inflammatory skin disorder, is poorly documented. In the present study, we examined the immunological effect of drinking HW onDermatophagoides farinae-induced AD-like skin in NC/Nga mice. Mice were administered with HW and purified water (PW) for 25 days. We evaluated the serum concentration of pro-inflammatory (TNF-α), Th1 (IFN-γ, IL-2, and IL-12p70), Th2 (IL-4, IL-5, and IL-10), and cytokine expressed by both subsets (GM-CSF) to assess their possible relationship to the severity of AD. The serum levels of cytokines such as IL-10, TNF-α, IL-12p70, and GM-CSF of mice administered with HW was significantly reduced as compared to PW group. The results suggest that HW affects allergic contact dermatitis through modulation of Th1 and Th2 responses in NC/Nga mice. This is the first note on the drinking effect of HW on AD, clinically implying a promising potential remedy for treatment of AD.

Objective: Triple-negative breast cancer (TNBC) accounts for 12-24% of total breast cancer, and contributes to the more aggressive, therapy-resistant and poorer outcomes. Our analysis based on The Cancer Genome Atlas (TCGA) indicated that basal-like BC subtype representing TNBC has enriched expression profiles for epidermal growth factor receptor 1 (EGFR) and transforming growth factor alpha (TGFá) compared to other subtypes. In addition, TNBC has a higher proinflammatory index compared to non-TNBC. Here we report that the proinflammatory chemokines such as CXCL1-3 and 8 are highly expressed in human TNBC cells and might be potentiated by TGFá-EGFR axis that contributes to cancer progression of TNBC. Methods: To gauge the role of TGFá-EGFR axis as a proinflammatory driver in TNBC cells, we first checked the expression profiles for EGFR family such as EGFR, HER2, ErbB3, and ErbB4 between TNBC (MCF10A, MB468, MB231, and BT549) and non-TNBC cells (MCF7, T47D). In addition, the expression levels of downstream signaling for EGFR (Akt/Erk) were measured by western blot. To dissect the role of TGFá-EGFR axis in enhancing proinflammatory index in TNBC cells, we utilized a more comprehensive study of the chemokines and chemokine receptors using human chemokine PCR array. Finally, to further confirm the role of TGFá-EGFR axis in inflammatory burden and cancer progression in TNBC, we used EGFR inhibitor and its downstream targets. Results: TNBC cells expressed more proinflammatory chemokines such as CXCL1-3 and 8 compared to non-TNBC cells. TNBC cells (MB468, MB231, and BT549) showed higher expression of EGFR which led to higher Akt activation as compared to non-TNBC cells. However, Erk is only activated in MB231. To dissect the involvement of Akt, expression of Akt isoforms in TNBC cells was accessed and Akt1 is the predominant isoform expressed in TNBC cells. To further assess the involvement of Akt1 in proinflammatory burden in TNBC cells, we used a commercial siRNA of Akt1 to knockdown Akt1. Knockdown of Akt1 significantly reduced the CXCL2 promoter activity. In addition, afatinib (an EGFR inhibitor) and MK2206 (an Akt inhibitor) significantly reduced the CXCL2 promoter activity. Conclusion: Thus, higher expression of proinflammatory chemokines CXCL1-3, and 8, via TGFá-EGFR axis-activated Akt, contributes to the inflammatory burden, probably promoting cancer progression, thereby followed by the overall high mortality in TNBC compared to non-TNBC. Citation Format: Rosa Mistica C. Ignacio, Carla Gibbs, Eun-Sook Lee, Deok-Soo Son. Involvement of proinflammatory chemokines in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 726.