Myeloid derived suppressor cells and the release of micro-metastases from dormancy.

Metastasis is the primary cause of cancer mortality and an improved understanding of its pathology is critical to the development of novel therapeutic approaches. Mechanism-based therapeutic strategies require insight into the timing of tumor cell dissemination, seeding of distant organs, formation of occult lesions and critically, their release from dormancy. Due to imaging limitations, primary tumors can only be detected when they reach a relatively large size (e.g. > 1 cm3), which, based on our understanding of tumor evolution, occurs approximately 10 years and about 30 doubling times following tumor initiation. Genomic profiling of paired primary tumors and metastases has suggested that tumor seeding at secondary sites occurs early during tumor progression and frequently, years prior to clinical diagnosis. Following seeding, tumor cells may enter into and remain in a dormant state, and if they survive and are released from dormancy, they can proliferate into an overt lesion. The timeline of tumor initiation and metastatic dormancy is regulated by tumor interactions with its microenvironment, angiogenesis, and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Therefore, a better understanding of the cellular interactions responsible for immune evasion and/or tumor cell release from dormancy would facilitate the development of therapeutics targeted against this critical part of tumor progression. The immunosuppressive mechanisms mediated by myeloid-derived suppressor cells (MDSCs) contribute to tumor progression and, we posit, promote tumor cell escape from CTL-associated dormancy. Thus, while clinical and translational research has demonstrated a role for MDSCs in facilitating tumor progression and metastasis through tumor escape from adoptive and innate immune responses (T-, natural killer and B-cell responses), few studies have considered the role of MDSCs in tumor release from dormancy. In this review, we discuss MDSC expansion, driven by tumor burden associated growth factor secretion and their role in tumor cell escape from dormancy, resulting in manifest metastases. Thus, the therapeutic strategies to inhibit MDSC expansion and function may provide an approach to delay metastatic relapse and prolong the survival of patients with advanced malignancies.

A Perspective on Therapeutic Pan-Resistance in Metastatic Cancer.

Metastatic spread represents the leading cause of disease-related mortality among cancer patients. Many cancer patients suffer from metastatic relapse years or even decades after radical surgery for the primary tumor. This clinical phenomenon is explained by the early dissemination of cancer cells followed by a long period of dormancy. Although dormancy could be viewed as a window of opportunity for therapeutic interventions, dormant disseminated cancer cells and micrometastases, as well as emergent outgrowing macrometastases, exhibit a generalized, innate resistance to chemotherapy and even immunotherapy. This therapeutic pan-resistance, on top of other adaptive responses to targeted agents such as acquired mutations and lineage plasticity, underpins the current difficulties in eradicating cancer. In the present review, we attempt to provide a framework to understand the underlying biology of this major issue.

Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer­associated fibroblasts.

Cancer­associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor­stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number. In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.

Outcomes of cancer surgery after inhalational and intravenous anesthesia: A systematic review.

Perioperative factors are probably essential for different oncological outcomes. This systematic review investigates the literature concerning overall mortality and postoperative complications after cancer surgery with inhalational (INHA) and intravenous anesthesia (TIVA). A search was conducted according to the PRISMA guidelines, including studies with patients undergoing surgery for cancer and where TIVA was compared with INHA. Two investigators identified relevant papers in the databases: PubMed, Scopus, EMBASE and the Cochrane Library. Risks of bias assessment tools from the Cochrane Collaboration were used for evaluating quality of evidence. Eight studies with a total of 10,696 patients were included. Four studies reported data regarding overall mortality and four studies reported data regarding postoperative complications. Evidence was evaluated to be of moderate to serious risk of bias. Three retrospective studies presented a hazard ratio (HR) adjusting for several confounders. One study reported an increased overall mortality after INHA with a HR of 1.47 (95% CI 1.31-1.64, p≤0.001), while another study reported a tendency of decreased overall mortality after TIVA (HR 0.85, 95% CI 0.72-1.00, p=0.051). A third study showed no difference in the overall mortality, but prolonged recurrence-free survival after TIVA with a HR of 0.48 (95% CI 0.27-0.86, p=0.014). In one study, the rate of pulmonary complications was significantly higher after INHA compared with TIVA, while other postoperative complications were comparable. There are currently four propensity-adjusted retrospective studies indicating that TIVA might be the preferred anesthetic choice in cancer surgery. However, evidence is currently of low quality and randomized clinical trials are required for further investigation.

Proposed new lymphology combined with lymphatic physiology, innate immunology, and oncology.

As one of the lymphatic functions, it is well known that the transport and drainage of hydrophilic substances including plasma protein through the lymphatic system play pivotal roles in maintaining the homeostasis of the internal environment between the cells in tissues in collaboration with the exchange of the substances through the blood capillaries and venules. The physiological functions of the lymphatic system have been studied by many investigations of microcirculation, i.e., Yoffey and Courtice, Ruszunyak et al., Földie and Casley-Smigh et al., Roddie, Schmid-Schönbein et al., and Ohhashi et al. On the other hand, it is also well known that the initial clinical signs of primary diseases such as inflammation, tumors, and circulatory disorders including infarction and thrombosis appear as functional abnormalities of the internal environment in tissues. These abnormalities of the functions are strongly related to immunological defense reactions around the internal environment and abnormal actions of the transport and drainage of the lymphatic system. Taking into consideration the current inspired findings in lymphatic physiology, innate immunology, and oncology, we have proposed a new lymphology combined with new knowledge of the three above-mentioned academic fields from a defense mechanism points of view. In this review, we would like to demonstrate comprehensively our latest studies related to the possibility of establishing a new lymphology, hoping the readers will evaluate this possibility.

Regulatory T-cells and micrometastasis in lymph nodes of stage I NSCLC.

BACKGROUND: Regulatory T-cells (Tregs) have a pivotal role not only in abrogating autoimmune disease, but also in tumor immune escape. The purpose of the present study was to evaluate the clinical significance of the relative expression of forkhead/winged helix transcription factor (FOXP3) and micrometastasis in the regional lymph nodes (RLNs) of patients with stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The RLNs in 131 patients who underwent complete surgical resection for stage I NSCLC were collected at the time of surgery. The relative expression levels of FOXP3 and cytokeratin 19 (CK19) in RLNs were determined by quantitative RT-PCR. RESULTS: The pathological stage was diagnosed as stage IA in 97 patients (74.0%) and stage IB in 34 patients (26.0%). The relative expression levels of FOXP3 and CK19 in the RLNs were 0.062±0.0083% and 0.025±0.056%, respectively. The relative expression of FOXP3 tended to increase with increasing relative expression of CK19. The five-year overall survival rate of the patients with low expression of FOXP3 was better (90.3%) than that of patients with high expression (79.3%) (p=0.0419). A multivariate analysis using the significant variables (gender, age, histology and FOXP3 expression) showed that the FOXP3 expression in RLNs was a significant independent prognostic factor. CONCLUSION: The expression of CK19 tended to be positively correlated with the expression of FOXP3. High expression of FOXP3 in RLNs was a significant unfavorable prognostic factor in patients with stage I NSCLC.

Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates.

Drug-resistant micrometastases that escape standard therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-infrared chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photocytotoxicity and resolution of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of "tumor-targeted, activatable photoimmunotherapy" in a mouse model of peritoneal carcinomatosis. By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease.

Can immunity to breast cancer eliminate residual micrometastases?

An effective immune response has the potential for breast cancer sterilization with marked reduction in the potential for disease relapse. Adaptive type I immune cells uniquely have the capability of (i) cytotoxic T-cell activation and proliferation until all antigen expressing cells are eradicated, (ii) traversing endothelial barriers to penetrate tumor deposits wherever they occur, and (iii) immunologic memory, which allows the persistence of destructive immunity over the years it may take for breast cancer micrometastases to become clinically evident. Numerous recent investigations suggest that some breast cancers stimulate the type of immunity that results in a decreased risk of relapse. Moreover, the endogenous type I tumor microenvironment or type I immunity induced by drugs or biologic agents may improve response to standard therapies, further lowering the probability of disease recurrence.