Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy

Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the “inflamed” immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment

The Case for Enhanced Data Collection of Gun Type

Background: National surveillance systems have differentiated long guns into rifles and shotguns but fail to do so for handgun type. We sought to determine whether specific gun type data could be collected and whether knowledge of specific gun types (rifle, shotgun, pistol, revolver) could be used to distinguish gun homicide victims with respect to important injury parameters such as number of wounds. Methods: Data on gun fatalities over a 5-year period in three communities were abstracted from medical examiner/coroner, police, and crime laboratory records. Results: Gun type was obtained for 92% of 490 guns linked to 405 gun homicides. Handguns were associated with more wounds per gun than long guns (p = 0.001) and more entry wounds per gun than long guns (p = 0.002). Among handguns, pistols were associated with more wounds per gun (p \u3c 0.001) and entry wounds per gun (p = 0.001) than revolvers. These same associations were not found among specific long gun types (i.e., rifles and shotguns). Conclusion: Our findings demonstrate that information about gun type can be obtained and that significant differences exist in wounds per gun between long guns and handguns and between pistols and revolvers. Classification of long guns into rifles and shotguns and handguns into pistols and revolvers should be included in local, regional, and national data collection systems

Recruitment of Community-Residing Youth Into Studies on Aggression

Recruitment of community-based youth into studies is challenging. We examined access issues, minority status, and personal costs of participation for a study of children with aggressive behaviors, designed to identify which ones are at risk for future violent behaviors, to identify protective factors, and to test interventions to reduce aggression. Of 1,038 contacts, 112 declined, 239 could not be re-contacted, and 124 were ineligible. Three hundred and fifty of 563 scheduled child-parent dyads completed intake assessment. Most were recruited through targeted mailings (33%) and community flyers (22%), 12% through regional news advertisement, 8% by Craigslist, and 5% through healthcare providers/clinics. Factors contributing to enrollment rates by zip code showed the percentage of Black residents per zip code and targeted mailings positively contributed (Beta = .200 & .419, respectively) and estimated transit travel time negatively contributed (Beta =.299) to enrollment rates (R2 = 0.562). Targeted mailings proved to be the most efficient strategy in successful recruitment

Revealing the role of the autonomic nervous system in the development and maintenance of Goldblatt hypertension in rats

Despite extensive use of the renovascular/Goldblatt model of hypertension-2K-1C, and the use of renal denervation to treat drug resistant hypertensive patients, autonomic mechanisms that underpin the maintenance of this hypertension are important yet remain unclear. Our aim was to analyse cardiovascular autonomic function by power spectral density analysis of both arterial pressure and pulse interval measured continuously by radio telemetry for 6 weeks after renal artery clipping. Mean arterial pressure increased from 106 +/- 5 to 185 +/- 2 mm Hg during 5 weeks post clipping when it stabilized. A tachycardia developed during the 4th week, which plateaued between weeks 5 and 6. the gain of the cardiac vagal baroreflex decreased immediately after clipping and continued to do so until the 5th week when it plateaued (from -2.4 +/- 0.09 to -0.8 +/- 0.04 bpm/mm Hg; P < 0.05). A similar time course of changes in the high frequency power spectral density of the pulse interval was observed (decrease from 13.4 +/- 0.6 to 8.3 +/- 0.01 ms(2); P < 0.05). There was an increase in both the very low frequency and low frequency components of systolic blood pressure that occurred 3 and 4 weeks after clipping, respectively. Thus, we show for the first time the temporal profile of autonomic mechanisms underpinning the initiation, development and maintenance of renovascular hypertension including: an immediate depression of cardiac baroreflex gain followed by a delayed cardiac sympathetic predominance; elevated sympathetic vasomotor drive occurring after the initiation of the hypertension but coinciding during its mid-development and maintenance. (C) 2014 the Authors. Published by Elsevier B.V.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)British Heart FoundationNIHUniv Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, EnglandUniversidade Federal de São Paulo, UNIFESP, Dept Physiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Dept Physiol, BR-04023062 São Paulo, BrazilWeb of Scienc

Effective Trauma Center Partnerships to Address Firearm Injury: A New Paradigm

Background: Firearm violence is the second leading cause of injury-related death. This study examined the use of local trauma centers as lead organizations in their communities to address firearm injury. Methods: Three trauma centers in cities with populations less than 100,000 were linked with a university-based firearm injury research center. A trauma surgeon director and coordinator partnered with communities, recruited and directed advisory boards, established a local firearm injury surveillance system, and informed communities using community-specific profiles. Primary process and outcome measures included completeness of data, development of community-specific profiles, number of data-driven consumer media pieces, number of meetings to inform policy makers, and an analysis of problems encountered. Results: Local trauma centers in smaller communities implemented a firearm injury surveillance system, produced community-specific injury profiles, and engaged community leaders and policy makers to address firearm injury. Community-specific profiles demonstrated consistent firearm suicide rates (6.58–6.82 per 100,000) but variation in firearm homicide rates (1.08–12.5 per 100,000) across sites. There were 63 data-driven media pieces and 18 forums to inform community leaders and policy makers. Completeness of data elements ranged from 57.1% to 100%. Problems experienced were disconnected data sources, multiple data owners, potential for political fallout, limited trauma center data, skills sets of medical professionals, and sustainability. Conclusion: Trauma centers, when provided resources and support, with the model described, can function as lead organizations in partnering with the community to acquire and use community-specific data for local firearm injury prevention

Proteolytic Cleavage and Activation of pro-Macrophage-Stimulating Protein and Upregulation of its Receptor in Tissue Injury

Macrophage stimulating protein (MSP) exists in blood as inactive pro-MSP. Cleavage yields active MSP, the ligand for a membrane receptor (RON) that is expressed on keratinocytes as well as macrophages. Because both cells have roles in tissue injury, we looked for active MSP and expressed RON in wounds. Concentration of pro-MSP + MSP in wound exudates was in the range for optimal activity. Western blot showed that MSP comprised about half the total, in contrast to less than 10% of the total in blood plasma. The presence of MSP was attributed to an exudate pro-MSP convertase that had an inhibitor profile consistent with a trypsin-like serine protease. Exudate evoked morphologic changes in macrophages in vitro like that of MSP. Removal of this activity by an anti-MSP column shows that exudate stimulation of macrophages is due to MSP. RON was infrequently detected in normal skin. RON protein was markedly upregulated in burn wound epidermis and accessory structures, in proliferating cells or differentiated cells, or both. RON was also detected on macrophages and capillaries. Tissue injury leads to cleavage of pro-MSP to MSP, which has potential to act on keratinocytes, macrophages, and capillaries, all components of the wound healing response

Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression

By reverse transcriptaseâ polymerase chain reaction, enzymelinked immunosorbent assay, and immunohistochemistry, MGSAâ α, â β, â γ, and CXCR2 mRNA expression and proteins are detected in 7 out of 10 human melanoma lesions. The biological consequence of constitutive expression of the MGSA/GRO chemokine in immortalized melanocytes was tested in SCID and nude mouse models. Continuous expression of MGSA/GROâ α, â β, or â γ in immortalized melanâ a mouse melanocytes results in nearly 100% tumor formation for each of the clones tested, whereas clones expressing only the neomycin resistance vector form tumors <10% of the time. Moreover, antibodies to the MGSA/GRO proteins slow or inhibit the formation of tumors in the SCID mouse model and block the angiogenic response to conditioned medium from the tumorâ producing clones. Transcription of the MGSA/ GRO chemokines is regulated by an enhancesomelike complex comprised of the nuclear factorâ κB (NFâ κB), HMG(I)Y, IUR, and Sp1 elements. In Hs294T melanoma cells the half life of the IκB protein is shortened in comparison to normal retinal epithelial cells, facilitating the endogenous nuclear localization of NFâ κB. We propose that this endogenous nuclear NFâ κB, working in concert with the 115â κDa IURâ binding factor, promotes constitutive expression of MGSA/GRO genes. J. Leukoc. Biol.62: 588â 597; 1997.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141559/1/jlb0588.pd

The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma

Continuous expression of the MGSA/GROα, β, or γ chemokine bestows tumorâ forming capacity to the immortalized murine melanocyte cell line, melanâ a. The mechanism for this transformation is unclear, although both autocrine and paracrine processes are possible because melanâ a cells as well as endothelial cells express a low level of the receptor for this ligand. To further define the role of MGSA/GRO proteins in melanocyte transformation, two types of experiments were designed to neutralize the biological effects of MGSA/GRO in the transfected melanâ a clones: (1) the effect of neutralizing antiserum to MGSA/GRO proteins on melanâ a tumor growth was assessed; (2) the tumorâ forming capacity of melanâ a clones expressing ELR motifâ mutated forms of MGSA/GRO with compromised receptor affinity was compared to the tumorâ forming capacity of clones expressing wildâ type MGSA/GRO. These experiments revealed that SCID mice inoculated with MGSA/GROαâ or γâ expressing melanâ a cells and subsequently treated with antiserum to the respective chemokine exhibited decreased tumor growth. This reduction in tumor growth was accompanied by declining angiogenic activity in MGSA/GROγâ expressing tumors. Moreover, athymic nude mice injected with melanâ a cells expressing ELRâ mutant forms of MGSA/GROα exhibited markedly impaired tumorâ forming capacity compared with those mice injected with melanâ a clones expressing wildâ type MGSA/GRO. These data suggest that continuous expression of MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of microvessels into the tumor (paracrine) and by affecting melanocyte growth (autocrine). J. Leukoc. Biol. 67: 53â 62; 2000.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142059/1/jlb0053.pd

CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene α), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC