Cancers adopt diverse strategies to safeguard their survival, which often involve blinding or incapacitating the immune response, thereby gaining battleground advantage against the host. In immune responses against cancer, an important stimulatory lymphocyte receptor is NKG2D because the tumor-associated expression of its ligands promotes destruction of malignant cells. However, with advanced human cancers profound changes unfold, wherein NKG2D and its ligands are targeted or exploited for immune evasion and suppression. This negative imprinting on the immune system may be accompanied by another functional state wherein cancer cells co-opt expression of NKG2D to complement the presence of its ligands for self-stimulation of tumor growth and presumably malignant progression. This review emphasizes these conflicting functional dynamics at the immunity – cancer biology interface in humans, within an overview of the immunobiology of NKG2D and mechanisms underlying the regulation of its ligands in cancer, with reference to instructive clinical observations and translational approaches.

This work contributes to a deeper understanding of hypoxic regulatory mechanisms in CSCs and will help devise novel therapies against prostate cancer.

Multi‐walled carbon nanotube‐7 (MWCNT‐7) fibers are biopersistent and have a structure similar to asbestos. MWCNT‐7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT‐7 developed lung tumors. MWCNT‐N, which is similar to MWCNT‐7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans‐tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT‐7 when administered by the TIPS method. Ten‐week‐old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 μg/mL MWCNT‐7 or 0.250 μg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT‐7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT‐7 group was significantly higher than in the vehicle or crocidolite groups.

Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.

Purpose: Although prognostic and predictive factors in ovarian cancer have been extensively studied for decades, only few have been identified and introduced to clinical practice. Here, we evaluate hVps37A (HCRP1) as a possible novel predictive marker for ovarian cancer. hVps37A was originally described as a member of the membrane-trafficking ESCRT-I complex mediating the internalization and degradation of ubiquitinated membrane receptors.Experimental Design: We analyzed an ovarian cancer tissue microarray for HCRP1, EGFR, and HER2 expression. We used a tetracycline inducible ovarian cancer cell culture model to show the effects of hVps37A knockdown in vitro and in vivo. In addition, we studied the effects of epidermal growth factor receptor (EGFR) inhibitors cetuximab and lapatinib on ovarian cancer cells under conditions of hVps37A knockdown.Results: We find that hVps37A is significantly downregulated in ovarian cancer and modifies the prognostic value of EGFR and HER2 expression. In addition, hVps37A downregulation in ovarian cancer cells leads to cytoplasmic pEGFR retention and hyperactivation of downstream pathways and is associated with enhanced xenograft growth in nude mice and invasion of the collagen matrix. Furthermore, due to subsequent sustained Akt-and MAPK-pathway activation, hVps37A-deficient cells become irresponsive to inhibition by the therapeutic antibody cetuximab.Conclusion: We propose that hVps37A status could become a novel prognostic and therapeutic marker for EGFR or HER2 driven tumors. Clin Cancer Res; 17(24); 7816-27. Ó2011 AACR.

Potassium octatitanate fibers (K2O·8TiO2, POT fibers) are widely used as an alternative to asbestos. We investigated the pulmonary and pleural toxicity of POT fibers with reference to 2 non‐fibrous titanium dioxide nanoparticles (nTiO 2), photoreactive anatase (a‐nTiO 2) and inert rutile (r‐nTiO 2). Ten‐week‐old male F344 rats were given 0.5 mL of 250 μg/mL suspensions of POT fibers, a‐nTiO 2, or r‐nTiO 2, 8 times (1 mg/rat) over a 15‐day period by trans‐tracheal intrapulmonary spraying (TIPS). Rats were killed at 6 hours and at 4 weeks after the last TIPS dose. Alveolar macrophages were significantly increased in all treatment groups at 6 hours and at 4 weeks. At week 4, a‐nTiO 2 and r‐nTiO 2 were largely cleared from the lung whereas a major fraction of POT fibers were not cleared. In the bronchoalveolar lavage, alkaline phosphatase activity was elevated in all treatment groups, and lactate dehydrogenase (LDH) activity was elevated in the a‐nTiO 2 and POT groups. In lung tissue, oxidative stress index and proliferating cell nuclear antigen (PCNA) index were elevated in the a‐nTiO 2 and POT groups, and there was a significant elevation in C‐C motif chemokine ligand 2 (CCL2) mRNA and protein in the POT group. In pleural cavity lavage, total protein was elevated in all 3 treatment groups, and LDH activity was elevated in the a‐nTiO 2 and POT groups. Importantly, the PCNA index of the visceral mesothelium was increased in the POT group. Overall, POT fibers had greater biopersistence, induced higher expression of CCL2, and provoked a stronger tissue response than a‐nTiO 2 or r‐nTiO 2.

Background Multi-walled carbon nanotubes can be divided into two general subtypes: tangled and straight. MWCNT-N (60 nm in diameter) and MWCNT-7 (80–90 nm in diameter) are straight-type MWCNTs, and similarly to asbestos, both are carcinogenic to the lung and pleura when administered to rats via the airway. Injection of straight-type MWCNTs into the peritoneal cavity also induces the development of mesothelioma, however, injection of tangled-type MWCNTs into the peritoneal cavity does not induce carcinogenesis. To investigate these effects in the lung we conducted a 2-year comparative study of the potential carcinogenicities of a straight-type MWCNT, MWCNT-A (approximately 150 nm in diameter), and a tangled-type MWCNT, MWCNT-B (7.4 nm in diameter) after administration into the rat lung. Crocidolite asbestos was used as the reference material, and rats administered vehicle were used as the controls. Test materials were administered by intra-Tracheal Intra-Pulmonary Spraying (TIPS) once a week over a 7 week period (8 administrations from day 1 to day 50), followed by a 2-year observation period without further treatment. Rats were administered total doses of 0.5 or 1.0 mg MWCNT-A and MWCNT-B or 1.0 mg asbestos. Results There was no difference in survival between any of the groups. The rats administered MWCNT-A or asbestos did not have a significant increase in bronchiolo-alveolar hyperplasia or tumors in the lung. However, the rats administered MWCNT-B did have significantly elevated incidences of bronchiolo-alveolar hyperplasia and tumors in the lung: the incidence of bronchiolo-alveolar hyperplasia was 0/20, 6/20, and 9/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively, and the incidence of adenoma and adenocarcinoma combined was 1/19, 5/20, and 7/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively. Malignant pleural mesothelioma was not induced in any of the groups. Conclusions The results of this initial study indicate that tangled-type MWCNT-B is carcinogenic to the rat lung when administered via the airway, and that straight-type MWCNT-A did not have higher carcinogenic potential in the rat lung than tangled-type MWCNT-B.

BACKGROUND: TRAIL (tumor necrosis factor related apoptosis-inducing ligand) is involved in tumor immune surveillance and, thus, may be a potential cancer therapy. TRAIL expression in the tumor microenvironment has been shown to impact cancer survival in multiple tumor types, including ovarian cancer. We studied TRAIL expression and outcomes in patients with prostate cancer. METHODS: A tissue microarray (TMA) of 200 prostate cancer patients and benign prostate tissue controls was used to assess the epithelial and stromal protein expression of TRAIL, death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and the FLICE inhibitory protein (FLIP L ). We correlated these expression patterns with clinicopathological parameters and determined its impact on recurrence-free survival. RESULTS: Nearly all (99.5%) prostate cancer tissues examined displayed either decreased expression of pro-apoptotic TRAIL receptors, increased FLIP L expression, or both. We observed elevated death receptor, decoy receptor, FLIP L , and epithelial TRAIL expression in prostate cancer epithelium. TRAIL expression in the stromal tumor microenvironment surrounding the prostate cancer was markedly lower. Elevated TRAIL expression in the tumor microenvironment was also significantly associated with increased recurrence-free survival (P ¼ .014), after controlling for other prognostic markers. In contrast, epithelial expression of TRAIL did not have an effect on overall survival. CONCLUSIONS: Expression of the components of the pro-apoptotic TRAIL pathway is altered in prostate cancer. Moreover, TRAIL expression in the tumor microenvironment may affect recurrence-free survival rate of prostate cancer patients. Consequently, these results may be useful in devising future therapeutic strategies targeting the TRAIL pathway in prostate cancer.