Redefining Expertise and Evidence in Global Implementation Research.

The theme for the 11th Annual Symposium on Global Cancer Research, co-convened with partners by the U.S. NCI Center for Global Health is "Closing the Research-to-Implementation Gap." Here, we reflect on the evolving role of implementation science from the lens of the needs of low- and middle-income countries. We highlight the importance for stronger and sustained engagement of implementation scientists and cancer control and prevention practitioners to enable more context-relevant co-design of implementation plans and strategies. We argue that deep learning from embedded implementation research through inductive analytic approaches is a critical first step to acceleration of evidence-to-practice translation and suggest an important role for systems approaches to facilitate this transition.

Building Capacity for Global Cancer Research: Existing Opportunities and Future Directions.

Cancer incidence and mortality are increasing in low- and middle-income countries (LMICs), where more than 75% of global cancer burden will occur by the year 2040. The primary drivers of cancer morbidity and mortality in LMICs are environmental and behavioral risk factors, inadequate prevention and early detection services, presence of comorbidities, and poor access to treatment and palliation. These same drivers also contribute to marked cancer health disparities in high-income countries. Studying cancer in LMICs provides opportunities to better understand and address these drivers to benefit populations worldwide, and reflecting this, global oncology as an academic discipline has grown substantially in recent years. However, sustaining this growth requires a uniquely trained workforce with the skills to pursue relevant, rigorous, and equitable global oncology research. Despite this need, dedicated global cancer research training programs remain somewhat nascent and uncoordinated. In this paper, we discuss efforts to address these gaps in global cancer research training at the US National Institutes of Health.

Early-life exposures to infectious agents and later cancer development.

There is a growing understanding that several infectious agents are acquired in early life and this is the reason why available vaccines target the new born, infants, and adolescents. Infectious agents are associated with cancer development and it is estimated that about 20% of the world's cancer burden is attributed to infectious agents. There is a growing evidence that certain infectious agents acquired in early life can give rise to cancer development, but estimates of the cancer burden from this early-life acquisition is unknown. In this article, we have selected five cancers (cervical, liver, Burkitt's lymphoma-leukemia, nasopharyngeal carcinoma, and adult T-cell leukemia-lymphoma) and examine their links to infectious agents (HPV, HBV, HCV, EBV, and HTLV-1) acquired in early life. For these agents, the acquisition in early life is from mother-to-child transmission, perinatal contact (with genital tract secretions, amniotic fluids, blood, and breast milk), saliva, sexual intercourse, and blood transfusion. We also discuss prevention strategies, address future directions, and propose mechanisms of action after a long latency period from the time of acquisition of the infectious agent in early life to cancer development.

Cancer-associated infectious agents and epigenetic regulation.

Infectious agents are one of the factors which contribute to cancer development. Few examples include human papilloma virus in cervical cancer, hepatitis virus in hepatocellular carcinoma, herpes virus in Kaposi's sarcoma, Epstein-Barr virus in nasopharyngeal carcinoma, human T-cell lymphotropic virus type-1 (HTLV-1) in T-cell leukemia and lymphoma, Helicobacter pylori in gastric cancer. These agents cause genomic instability in the host and most of them affect host immune system. Infectious agents may integrate in the host genome although their sit of integration is not fixed. Expression of some infectious agents involves epigenetic regulation by DNA methylation, histone modification, miRNA level alteration, and chromatin condensation. This chapter provides examples where epigenetic regulation has been reported in cancer-associated infectious agents. Epigenetic inhibitors and their potential in cancer control and treatment are also discussed.

Multiple infections and cancer: implications in epidemiology.

Approximately 18% of the global cancer burden has been attributed to infectious agents, with estimates ranging from 7% in developed countries to about 22% in developing countries. Chronic infections caused by the hepatitis B and C viruses, human papilloma viruses (HPV), and Helicobacter pylori (H. pylori) are reported to be responsible for approximately 15% of all human cancers. Interestingly, although many of the infectious agents that have been associated with cancer--such as HPV, Epstein-Barr virus (EBV), and H. pylori--are highly prevalent in the world, most infected individuals do not develop cancer but remain lifelong carriers. Malignancies associated with infectious agents may result from prolonged latency as a result of chronic infections. Pathogenic infections are necessary but are not sufficient for cancer initiation or progression. Cancer initiation may require additional cofactors, including secondary infections. Therefore, in patients with chronic infection with one agent, secondary co-infection with another agent may serve as an important co-factor that may cause cancer initiation and progression. Additionally, opportunistic co-infections could significantly inhibit response to cancer treatment and increase cancer mortality. Co-infections are relatively common in areas with a high prevalence of infectious agents, especially in developing countries. These co-infections can cause an imbalance in the host immune system by affecting persistence of and susceptibility to malignant infections. Several articles have been published that focus on infectious agents and cancer. In this article, we discuss the role of infectious agents in malignancies, highlight the role of multiple/co-infections in cancer etiology, and review implications for cancer epidemiology.

Real-time motion analysis reveals cell directionality as an indicator of breast cancer progression.

Cancer cells alter their migratory properties during tumor progression to invade surrounding tissues and metastasize to distant sites. However, it remains unclear how migratory behaviors differ between tumor cells of different malignancy and whether these migratory behaviors can be utilized to assess the malignant potential of tumor cells. Here, we analyzed the migratory behaviors of cell lines representing different stages of breast cancer progression using conventional migration assays or time-lapse imaging and particle image velocimetry (PIV) to capture migration dynamics. We find that the number of migrating cells in transwell assays, and the distance and speed of migration in unconstrained 2D assays, show no correlation with malignant potential. However, the directionality of cell motion during 2D migration nicely distinguishes benign and tumorigenic cell lines, with tumorigenic cell lines harboring less directed, more random motion. Furthermore, the migratory behaviors of epithelial sheets observed under basal conditions and in response to stimulation with epidermal growth factor (EGF) or lysophosphatitic acid (LPA) are distinct for each cell line with regard to cell speed, directionality, and spatiotemporal motion patterns. Surprisingly, treatment with LPA promotes a more cohesive, directional sheet movement in lung colony forming MCF10CA1a cells compared to basal conditions or EGF stimulation, implying that the LPA signaling pathway may alter the invasive potential of MCF10CA1a cells. Together, our findings identify cell directionality as a promising indicator for assessing the tumorigenic potential of breast cancer cell lines and show that LPA induces more cohesive motility in a subset of metastatic breast cancer cells.

Anti-peptidoglycan antibodies and Fcγ receptors are the key mediators of inflammation in Gram-positive sepsis.

Gram-positive bacteria are an important public health problem, but it is unclear how they cause systemic inflammation in sepsis. Our previous work showed that peptidoglycan (PGN) induced proinflammatory cytokines in human cells by binding to an unknown extracellular receptor, followed by phagocytosis leading to the generation of NOD ligands. In this study, we used flow cytometry to identify host factors that supported PGN binding to immune cells. PGN binding required plasma, and plasma from all tested healthy donors contained IgG recognizing PGN. Plasma depleted of IgG or of anti-PGN Abs did not support PGN binding or PGN-triggered cytokine production. Adding back intact but not F(ab')2 IgG restored binding and cytokine production. Transfection of HEK293 cells with FcγRIIA enabled PGN binding and phagocytosis. These data establish a key role for anti-PGN IgG and FcγRs in supporting inflammation to a major structural element of Gram-positive bacteria and suggest that anti-PGN IgG contributes to human pathology in Gram-positive sepsis.

Vav activation and function as a rac guanine nucleotide exchange factor in macrophage colony-stimulating factor-induced macrophage chemotaxis.

Signal transduction mediated by phosphatidylinositol 3-kinase (PI 3-kinase) is regulated by hydrolysis of its products, a function performed by the 145-kDa SH2 domain-containing inositol phosphatase (SHIP). Here, we show that bone marrow macrophages of SHIP(-/-) animals have elevated levels of phosphatidylinositol 3,4,5-trisphosphate [PI (3,4,5)P(3)] and displayed higher and more prolonged chemotactic responses to macrophage colony-stimulating factor (M-CSF) and elevated levels of F-actin relative to wild-type macrophages. We also found that the small GTPase Rac was constitutively active and its upstream activator Vav was constitutively phosphorylated in SHIP(-/-) macrophages. Furthermore, we show that Vav in wild-type macrophages is recruited to the membrane in a PI 3-kinase-dependent manner through the Vav pleckstrin homology domain upon M-CSF stimulation. Dominant inhibitory mutants of both Rac and Vav blocked chemotaxis. We conclude that Vav acts as a PI 3-kinase-dependent activator for Rac activation in macrophages stimulated with M-CSF and that SHIP regulates macrophage M-CSF-triggered chemotaxis by hydrolysis of PI (3,4,5)P(3).