Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory driven disease mouse models, we show that grapefruit-derived nanovectors (GNVs) coated with inflammatory related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of DSS induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that there is an overexpression of chemokines in diseased human tissue provides the rationale for using IGNVs to more directed delivery of therapeutic agents to inflammatory tumor sites and the use of IGNVs as personalized medicine for treatment of certain cancers.

The protein tyrosine phosphatase receptor PTPRN2 is expressed predominantly in endocrine and neuronal cells, where it functions in exocytosis. We found that its immature isoform proPTPRN2 is overexpressed in various cancers, including breast cancer. High proPTPRN2 expression was associated strongly with lymph node–positive breast cancer and poor clinical outcome. Loss of proPTPRN2 in breast cancer cells promoted apoptosis and blocked tumor formation in mice, whereas enforced expression of proPTPRN2 in nontransformed human mammary epithelial cells exerted a converse effect. Mechanistic investigations suggested that ProPTPRN2 elicited these effects through direct interaction with TRAF2, a hub scaffold protein for multiple kinase cascades, including ones that activate NF-κB. Overall, our results suggest PTPRN2 as a novel candidate biomarker and therapeutic target in breast cancer. Cancer Res; 75(9); 1–13. ©2015 AACR.

PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating the intracellular level of β-catenin and EGFR. Notably, PARK2 physically interacted with both β-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity-dependent manner. Finally, inspired by these newly identified tumor-suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt–β-catenin and EGFR–AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma. Cancer Res; 75(9); 1–13. ©2015 AACR.

The incidence of human papillomavirus (HPV)–positive oropharyngeal cancers is higher and increasing more rapidly among men than women in the United States for unknown reasons. We compared the epidemiology of oral oncogenic HPV infection between men and women ages 14 to 69 years (N = 9,480) within the U.S. National Health and Nutritional Examination Surveys (NHANES) 2009–2012. HPV presence was detected in oral DNA by PCR. Analyses were stratified by gender and used NHANES sample weights. Oral oncogenic HPV prevalence was higher among men than women (6.6% vs. 1.5%, P < 0.001), corresponding to 7.07 million men versus 1.54 million women with prevalent infection at any point in time during 2009–2012. Prevalence increased significantly with age, current smoking, and lifetime number of sexual partners for both genders (adjusted Ptrend < 0.02). However, men had more partners than women (mean = 18 vs. 7, P < 0.001). Although oncogenic HPV prevalence was similar for men and women with 0 to 1 lifetime partners, the male–female difference in prevalence significantly increased with number of lifetime partners (adjusted prevalence differences for none, 1, 2–5, 6–10, 11–20, and 20+ partners = 1.0%, 0.5%, 3.0%, 5.7%, 4.6%, and 9.3%, respectively). Importantly, the per-sexual partner increase in prevalence was significantly stronger among men than among women (adjusted synergy index = 3.3; 95% confidence interval, 1.1–9.7), and this increase plateaued at 25 lifetime partners among men versus10 partners among women. Our data suggest that the higher burden of oral oncogenic HPV infections and HPV-positive oropharyngeal cancers among men than women arises in part from higher number of lifetime sexual partners and stronger associations with sexual behaviors among men. Cancer Res; 75(12); 1–10. ©2015 AACR.

The incidence of human papillomavirus (HPV)-positive oropharyngeal cancers is higher and rising more rapidly among men than women in the United States (U.S.) for unknown reasons. We compared the epidemiology of oral oncogenic HPV infection between men and women aged 14-69 years (N=9,480) within the U.S. National Health and Nutritional Examination Surveys (NHANES) 2009-2012. HPV presence was detected in oral DNA by PCR. Analyses were stratified by gender and utilized NHANES sample weights. Oral oncogenic HPV prevalence was higher among men than women (6.6% vs. 1.5%, p<0.001), corresponding to 7.07 million men vs. 1.54 million women with prevalent infection at any point in time during 2009-2012. Prevalence increased significantly with age, current smoking, and lifetime number of sexual partners for both genders (adjusted p-trends<0.02). However, men had more partners than women (mean=18 vs. 7, p<0.001). Although oncogenic HPV prevalence was similar for men and women with 0-1 lifetime partners, the male-female difference in prevalence significantly increased with number of lifetime partners (adjusted prevalence differences for none, one, 2-to-5, 6-to-10, 11-to-20, and 20+ partners=1.0%, 0.5%, 3.0%, 5.7%, 4.6%, and 9.3%, respectively). Importantly, the per-sexual-partner increase in prevalence was significantly stronger among men than women (adjusted Synergy Index=3.3; 95%CI=1.1-9.7), and this increase plateaued at 25 lifetime partners among men vs.10 partners among women. Our data suggest that the higher burden of oral oncogenic HPV infections and HPV-positive oropharyngeal cancers among men than women arises in part from higher number of lifetime sexual partners and stronger associations with sexual behaviors among men.