Metastasis In Cancer Patients Research Articles

The role of ELK3 to regulate peritumoral lymphangiogenesis and VEGF-C production in triple negative breast cancer cells

Tumor-induced lymphangiogenesis, a major conduit for cancer cell dissemination from the primary tumor site to lymph nodes and beyond, eventually leads to metastasis in cancer patients. Given the recent evidence revealing that the suppression of ELK3 inhibits the metastasis of triple-negative breast cancer cells, we aimed to study the underlying mechanism of impaired metastasis in ELK3-suppressed MDA-MB-231 cells (ELK3 KD) with regard to lymphangiogenesis. We found that the secretome of ELK3 KD cells inhibited tube formation, whereas it promoted the migration and invasion of lymphatic endothelial cells (LECs) in vitro. In vivo analysis revealed that peritumoral lymphatic vessels were not developed around the xenografted tumors of ELK3 KD. We further revealed that the suppression of NF-κB signaling in ELK3 KD was the primary cause of the reduced VEGFC expression. Taken together, we suggest that ELK3 is an upstream regulator of the NF-κB signaling pathway, the inhibition of which leads to the suppression of peritumoral lymphatic vessel development, possibly due to a low VEGFC expression.

Custo-efetividade da radiocirurgia estereotáxica no tratamento de metástases cerebrais: revisão sistemática

ABSTRACT: Introduction – Brain metastases are a problem due to the oncologic disease, which significantly limit patient survival and their quality of life. The stereotactic radiosurgery discloses a non-invasive removal of brain metastases. Objectives – Verify if stereotactic radiosurgery is more cost-effective than alternative treatments for brain metastases in cancer patients. Methods – We conducted a systematic review of literature using EBSCO host and PubMed between 2005 and 2015. The search terms were ‘radiosurgery’, ‘brain’, ‘metastasis’, ‘economics’, and ‘cost-benefit analysis’. The survey revealed 57 potentially eligible articles for the review, which were subject to an evaluation in accordance with the defined selection criteria. Three articles were included in the review. Results and Discussion – The review showed stereotactic radiosurgery dominance in relation to the two alternatives studied (total radiation of the brain and traditional surgery for resection of metastases). This superiority is associated with lower costs and equal or better effects (effectiveness or utility) of stereotactic radiosurgery. The cost of stereotacticradiosurgery seems to be the key differentiator relative to alternative treatments, lower than them in the three studies. Conclusion – The associated costs and effects of using stereotactic radiosurgery suggest that this will be the best option for a more rational treatment of patients with brain metastases. However, the findings are limited because of the scarcity of evaluated studies in the review.

Detection of liver metastases in cancer patients with geographic fatty infiltration of the liver: the added value of contrast-enhanced sonography.

PurposeThe aim of this study is to assess the role of contrast-enhanced ultrasonography (CEUS) in the detection of liver metastases in cancer patients with geographic liver fatty deposition on greyscale ultrasonography (US).MethodsThirty-seven consecutive cancer patients (24 women and 13 men; age, 33 to 80 years; mean, 58.1 years) with geographic liver fatty deposition, but without any detectable focal liver lesion on greyscale US, underwent sulphur hexafluoride-enhanced US. Two readers reported by consensus the presence, size, and location of any detected lesion. All patients underwent magnetic resonance imaging (MRI) as a confirmatory study. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy were calculated.ResultsSeven focal liver lesions (size, 4 to 10 mm; mean, 6.1 mm) were detected in 4/37 patients (10.8%): four metastases (size, 5 to 10 mm; mean, 6.7 mm) were detected both by CEUS and MRI, with one hemangioma and two cysts (size range, 4 to 6 mm; mean, 5.3 mm) detected by MRI only. In 1/37 patients (2.7%), CEUS misdiagnosed geographic fatty change as three metastases. In 32/37 patients (86.5%), no lesions were detected. Sensitivity, specificity, PPV, NPV, and accuracy of CEUS were 100% (95% confidence Interval [CI], 1.000 to 1.000), 97.1% (95% CI, 0.914 to 1.027), 75%, 100%, and 97.3%, respectively. No statistically significant differences were found between CEUS and MRI in the detection of focal liver lesions (P=0.480), whereas both of them performed better than baseline US (P<0.001).ConclusionCEUS improves the detection of liver metastases in cancer patients with geographic liver fatty deposition on greyscale US.

Suppression of NADPH Oxidase Activity May Slow the Expansion of Osteolytic Bone Metastases.

Lysophosphatidic acid (LPA), generated in the microenvironment of cancer cells, can drive the proliferation, invasion, and migration of cancer cells by activating G protein-coupled LPA receptors. Moreover, in cancer cells that have metastasized to bone, LPA signaling can promote osteolysis by inducing cancer cell production of cytokines, such as IL-6 and IL-8, which can stimulate osteoblasts to secrete RANKL, a key promoter of osteoclastogenesis. Indeed, in cancers prone to metastasize to bone, LPA appears to be a major driver of the expansion of osteolytic bone metastases. Activation of NADPH oxidase has been shown to play a mediating role in the signaling pathways by which LPA, as well as RANKL, promote osteolysis. In addition, there is reason to suspect that Nox4 activation is a mediator of the feed-forward mechanism whereby release of TGF-beta from bone matrix by osteolysis promotes expression of PTHrP in cancer cells, and thereby induces further osteolysis. Hence, measures which can down-regulate NADPH oxidase activity may have potential for slowing the expansion of osteolytic bone metastases in cancer patients. Phycocyanin and high-dose statins may have utility in this regard, and could be contemplated as complements to bisphosphonates or denosumab for the prevention and control of osteolytic lesions. Ingestion of omega-3-rich flaxseed or fish oil may also have potential for controlling osteolysis in cancer patients.

Abstract 329: Reprogramming glucose metabolism and energy production with a small molecule HJC0152 suppresses breast cancer development and progression to metastasis

Abstract Currently there are no targeted therapeutic strategies for estrogen receptor (ER)-negative breast cancer (ENBC), which constitutes 30-40% of breast cancer cases and is prone to metastasize and recur. Distant metastasis accounts for 90% of cancer-associated deaths. The majority of deaths from breast cancer are caused by distant metastasis developed in lung, liver, bone, or brain. However, to date it remains a challenge and unmet need to treat existing metastasis and block new metastasis in cancer patients. Dysregulated glucose and energy metabolism is critically involved in the development and progression of various cancers via promoting aberrant cell growth, malignant transformation and metastasis, but the potential role of glucose/energy metabolism in ENBC progression and metastasis has scarcely been explored heretofore, thus representing a key knowledge gap and a potential avenue for anticancer targeting. A number of anticancer metabolic and biogenetic therapies have been developed, yet none of them has progressed to clinical use, due to their limited potency, specificity or drug properties such as toxicity and poor bioavailability. We recently identified a novel small molecule HJC0152 that significantly suppresses ENBC xenograft tumor growth and blocks ER-negative mammary tumor development in mouse models. HJC0152 treatment for 24-72 hours differentially modulates protein expression of HK1, PFK-L, PFKFB2, ENO2, PDH, PDK1, PGAM1 and ALDOA in a time-dependent manner. HJC0152 also regulates the transcription of genes involved in glucose and mitochondrial energy metabolism, including the subunits of mitochondrial respiratory chain complexes. Functional assessments of mitochondrial complexes demonstrate that HJC0152 significantly inhibits Complexes IV but increases Complex V (ATP synthase) function, while Complexes I and II function is minimally affected. Migration and invasion of MDA-MB-231 cells are significantly inhibited by HJC0152 treatment. In vivo, HJC0152 administrated either before, concurrent with or after tail vein injection of MDA-MB-231 cells dramatically blocks the development of lung macro- and micro-metastasis in all groups. These results suggest that HJC0152 can specifically reprogram/restore the dysregulated glucose metabolism by inducing specific glycolytic enzyme expression and mitochondrial respiratory chain function, likely via targeting one or more upstream signal molecule(s) that regulates glucose and energy metabolism, thereby suppressing breast cancer progression to metastasis. This work was supported by Grants P50 CA097007, P30DA028821, and R21MH093844 (J.Z.) from the NIH, CPRIT (J.Z.), John Sealy Memorial Endowment Fund (J.Z.), DFI Seed Grants from MD Anderson Cancer Center (Q.S.), and Holden Family Research Grant in Breast Cancer Prevention from the Prevent Cancer Foundation (Q.S). Citation Format: Hao Zou, Na Ye, Hui Pang, Dan Zhang, Ruping Yan, Haijun Chen, Guoshuai Cai, Lili Wang, Zhengduo Yang, Haiying Chen, Grace Xu, Yingchao Zhang, Ritu Arora, Ming Tan, Yongchang Wei, Jia Zhou, Qiang Shen. Reprogramming glucose metabolism and energy production with a small molecule HJC0152 suppresses breast cancer development and progression to metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 329.

Performance status versus anatomical recovery in metastatic disease: The role of palliative radiation treatment

Metastatic disease is a common complication of the most advanced malignancies. It may compromise the patients' quality of life, often posing a greater risk than the primary disease itself. Currently, several different therapeutic approaches are available to palliate or cure (single metastasis with primary neoplasm under control – radical surgery) secondary disease. In particular, radiation therapy is widely used, as it often leads to full or at least partial functional recovery, depending on the number and location of metastases. The aim of our study was to evaluate whether clinical improvement subsequent to radiation therapy may be related to anatomical recovery of the site of metastasis in cancer patients with metastatic disease. Given the heterogeneity of the diseases considered and the general complex conditions of the patients, a single method could not be used to evaluate the response to radiation treatment and its correlation with the performance status (PS). Thus, depending on the specific disease being assessed, we divided the patients into different groups. Patients in the same group were followed up with the same methods. This correlation was noted in a very high percentage of patients, predominantly in patients with vertebral and brain metastases. Moreover, we investigated the use of magnetic resonance imaging (MRI)-diffusion weighted imaging (DWI) in the study of spinal metastases. We propose its use in the local evaluation of vertebral secondary lesions, both in the diagnostic phase and during the assessment of treatment efficacy.

Tumor suppressive actions of the nuclear receptor corepressor 1

Nuclear Receptor Corepressor 1 (NCoR) is an important transcriptional regulator that interacts with nuclear receptors and other transcription factors. Recent results have shown the presence of inactivating mutations or deletions of the NCoR gene in human tumors. NCoR has a strong tumor suppressor activity, inhibiting invasion, metastasis formation and tumor growth in xenograft mouse models. These changes are associated to transcriptional inhibition of genes linked to bad prognosis and increased metastasis in cancer patients. NCoR loss causes a long-term repression of NCoR gene transcription, suggesting that NCoR deficiency in the cancer cell could be propagated playing a role in tumor progression in the absence of NCoR gene mutations. The thyroid hormone receptor TRβ increases NCoR expression and this induction is essential in mediating the anti-metastatic and tumor suppressive actions of the receptor. Since metastasis is the main cause of cancer-related deaths, these results define NCoR as a potential target for cancer therapy.

HOXB7 as a promising molecular marker for metastasis in cancers: a meta-analysis.

Numerous studies on carcinoma have revealed that the expression level of HOXB7 in cancerous tissues was significantly higher than that in noncancerous tissues. Elevated expression of HOXB7 is associated with the susceptibility to lymph node metastasis and distant metastasis in various tumors. In this study, a meta-analysis was performed to involve majority of relevant articles and explore the association of HOXB7 expression level with metastasis in cancer patients. Literature retrieval was conducted by searching in a number of electronic databases (up to December 1, 2015). The meta-analysis was conducted with RevMan 5.3 software and Stata SE12.0. A total of 1,532 patients with carcinoma from 14 studies were included in analysis. The results of meta-analysis demonstrated that lymph node metastasis was observed more frequently in the patients group with high expression level of HOXB7 than in the patients group with low expression level of HOXB7 (odds ratio =2.17, 95% CI: 1.74–2.71, P<0.00001, fixed-effects model). In addition, a similar result was observed in the association between HOXB7 expression and distant metastasis; the odds ratio was 1.77 (95% CI: 1.09–2.88, P=0.02, fixed-effects model). This meta-analysis demonstrated that the overexpression of HOXB7 was significantly associated with metastasis in cancer patients, which may be served as a common molecular marker for indicating cancer metastasis.

Added value of combined 18F-FDG PET/CT for detection of osseous metastases in cancer patients

PurposeThe goal of the study was to illustrate the added value of combined 18F-FDG PET/CT over isolated CT for detection of osseous metastases in cancer patients. Patients and methodsThe study included 53 patients divided into five groups of primary malignancies. 18F-PET/CT scans were performed. In this study, a lesion based analysis was performed in detailed retrograde matter for a total of 386 detected osseous lesions on CT and fused images of 18F-PET/CT. Statistical analysis including specificity, Sensitivity, negative predictive value (NPV) and positive predictive value (PPV) of each of these modalities was calculated. A final diagnosis of metastasis was confirmed by biopsy or by further clinical and radiologic workup. ResultsAccording to lesion based analysis, the 18F-PET/CT showed 100% sensitivity, 80.8% specificity, 98.6% PPV, 100% NPV and 98.7% accuracy compared with 93.9%, 34.6%, 95.2%, 29% and 89.9%, respectively, for CT. Significant improvement of the sensitivity and specificity was found in combined 18F-PET/CT than in CT alone. ConclusionCombined 18-F FDG PET/CT significantly improves the sensitivity and specificity of isolated CT for the detection of osseous metastases.

In vitro and ex vivo vanadium antitumor activity in (TGF-β)-induced EMT. Synergistic activity with carboplatin and correlation with tumor metastasis in cancer patients

Epithelial to mesenchymal transition (EMT) plays a key role in tumor progression and metastasis as a crucial event for cancer cells to trigger the metastatic niche. Transforming growth factor-β (TGF-β) has been shown to play an important role as an EMT inducer in various stages of carcinogenesis. Previous reports had shown that antitumor vanadium inhibits the metastatic potential of tumor cells by reducing MMP-2 expression and inducing ROS-dependent apoptosis. However, the role of vanadium in (TGF-β)-induced EMT remains unclear. In the present study, we report for the first time on the inhibitory effects of vanadium on (TGF-β)-mediated EMT followed by down-regulation of ex vivo cancer stem cell markers. The results demonstrate blockage of (TGF-β)-mediated EMT by vanadium and reduction in the mitochondrial potential of tumor cells linked to EMT and cancer metabolism. Furthermore, combination of vanadium and carboplatin (a) resulted in synergistic antitumor activity in ex vivo cell cultures, and (b) prompted G0/G1 cell cycle arrest and sensitization of tumor cells to carboplatin-induced apoptosis. Overall, the findings highlight the multifaceted antitumor action of vanadium and its synergistic antitumor efficacy with current chemotherapy drugs, knowledge that could be valuable for targeting cancer cell metabolism and cancer stem cell-mediated metastasis in aggressive chemoresistant tumors.

Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL.

Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P=0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.

Abstract B090: A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent

Abstract Liver metastases are a major common cause of mortality of patients with different types of cancer due to lack of effective treatment options. Anticancer immunotherapy provides an attractive approach for developing a more effective systemic therapy for patients with metastatic liver cancer. We generated a Toll-like receptor 5 (TLR5) agonistic agent entolimod™ (CBLB502), a pharmacologically optimized derivative of bacterial Salmonella flagellin that is now at advanced stage of clinical development as a medical countermeasure to reduce adverse side effects of radiation therapy. We also found that entolimod, in addition to its radioprotective properties, has anticancer effects against a variety of TLR5-positive tumors and TLR5-negative tumors residing in a TLR5-expressing environment such as the liver in mice. We hypothesized that entolimod can suppress tumor growth in a TLR5-responsive microenvironment such as the liver independently of the TLR5 status of tumor cells. We tested the therapeutic potential of entolimod against TLR5 responsive and non-responsive tumors using mouse triple negative 4T1 breast and CT26 colorectal adenocarcinoma models mimicking clinically occurring development of post-surgery liver metastases in cancer patients. Our results demonstrate that entolimod treatment was efficient in suppressing metastatic growth when injected systemically in both models. Investigating the mechanism of entolimod's antitumor activity we found that several major transcriptional factors, such as NF-κB, STAT-3 and AP-1, are rapidly activated in hepatocytes leading to a short-term neutrophilic infiltration and long-term NK cell accumulation and activation that coordinate CD8+ and CD4+ T cell immunity against liver metastases. This resulted in significant improvement of long-term tumor-free survival and durable, tumor-specific T cell memory. Importantly, unlike other TLR agonists entolimod is safe and does not show signs of septic shock even with systemic administration. Moreover, the results of two phase 1 clinical trials with 150 healthy volunteers and 26 patients with advanced cancers demonstrated good tolerability and safe profile of the response, which supports entolimod's potential as an immunotherapeutic agent. This also suggests that entolimod can be potentially combined with radiation, chemotherapeutic, targeted, and other immunotherapeutic agents to improve the efficacy of anticancer therapy. Citation Format: Craig Brackett, Bojidar Kojouharov, Sandra Gollnick, Andrei Gudkov, Lyudmila Burdelya. A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B090.

Detection of Circulating Tumor DNA in the Blood of Cancer Patients: An Important Tool in Cancer Chemoprevention.

Liquid biopsies represent novel promising tools to determine the impact of clonal heterogeneity on clinical outcomes with the potential to identify novel therapeutic targets in cancer patients. We developed a low-coverage whole-genome sequencing approach in order to noninvasively establish copy number aberrations in plasma DNA from metastasized cancer patients. Using plasma-Seq we were able to monitor genetic evolution including the acquirement of novel copy number changes, such as focal amplifications and chromosomal polysomies. The big advantage of our approach is that it can be performed on a benchtop sequencer, speed, and cost-effectiveness. Therefore, plasma-Seq represents an easy, fast, and affordable tool to provide the urgently needed genetic follow-up data. Here we describe our method including plasma DNA extraction, library preparation, and bioinformatic analyses.

SY20-6 - Transdiciplinary approach for skeletal metastases in cancer patients

In recent years, there has been increased attention on the management of skeletal metastases with the advent of bone modifying agents that provides clinical benefits. With advances in diagnostic imaging and cancer treatment, an increase in the number of cases has been observed, resulting in better prognosis and prolonged survival rates of those with skeletal metastases. Metastatic bone tumors are one of the clinical conditions among the various cancers; therefore, they are also handled by each department that is responsible for each kind of cancer. However, it affects the locomotive system and is different from other organ-specific cancers; therefore, a team approach, including orthopedics, is indispensable.In our hospital, we organized a team jointly with the department of rehabilitation that aimed at comprehensive care of skeletal metastases in April 2011. The team activity comprises bi-weekly skeletal-related events (SRE) conferences; rounds conducted by physicians, physical therapists (PT), and occupational therapists (OT); and a course of observation in an outpatient department. Staff members, from the responsible departments include Radiology, Department of Rehabilitation Medicine, PT/OT, aPalliative Care Team, Oncology, Dental Oral Surgery, Nurses, Pharmacists, and Medical Social Workers(MSW), and these experts get together to discuss problems and share information as required. During the SRE conference, responsible PTs and OTs present the current situation of patients' activities by video so that they are able to monitor their daily lifestyle activities. In the rounds, awareness is raised of more recent states, enabling cooperation with attending physicians and the ward nurses.With our efforts, we have been practicing approaches, including rehabilitation, to examine the orientation of the cases. In this study, we are also going to introduce a video of rehabilitation that has actually been performed. In recent years, there has been increased attention on the management of skeletal metastases with the advent of bone modifying agents that provides clinical benefits. With advances in diagnostic imaging and cancer treatment, an increase in the number of cases has been observed, resulting in better prognosis and prolonged survival rates of those with skeletal metastases. Metastatic bone tumors are one of the clinical conditions among the various cancers; therefore, they are also handled by each department that is responsible for each kind of cancer. However, it affects the locomotive system and is different from other organ-specific cancers; therefore, a team approach, including orthopedics, is indispensable. In our hospital, we organized a team jointly with the department of rehabilitation that aimed at comprehensive care of skeletal metastases in April 2011. The team activity comprises bi-weekly skeletal-related events (SRE) conferences; rounds conducted by physicians, physical therapists (PT), and occupational therapists (OT); and a course of observation in an outpatient department. Staff members, from the responsible departments include Radiology, Department of Rehabilitation Medicine, PT/OT, aPalliative Care Team, Oncology, Dental Oral Surgery, Nurses, Pharmacists, and Medical Social Workers(MSW), and these experts get together to discuss problems and share information as required. During the SRE conference, responsible PTs and OTs present the current situation of patients' activities by video so that they are able to monitor their daily lifestyle activities. In the rounds, awareness is raised of more recent states, enabling cooperation with attending physicians and the ward nurses. With our efforts, we have been practicing approaches, including rehabilitation, to examine the orientation of the cases. In this study, we are also going to introduce a video of rehabilitation that has actually been performed.

Cancer: Organ-seeking vesicles.

An analysis reveals that cancer cells remotely prepare distant sites for tumour spread in an organ-specific manner, by deploying organ-seeking extracellular vesicles. See Article p.329 How do cancer cells choose the next organ to target? David Lyden and colleagues show that extracellular vesicles (exosomes) that originate from tumour cells can preferentially fuse with specific resident cells of the target organs — lung, liver and brain — to prepare the site of metastasis. At a molecular level, expression of distinct combinations of integrin proteins on exosomes seems to mediate their targeting to one of the three organs. By blocking these integrins, the authors could reduce the uptake of the associated exosomes by the target organs and so the likelihood of metastasis. Moreover, the exosomal integrins could be used to predict organ-specific metastasis in cancer patients.

Neutrophils: important contributors to tumor progression and metastasis.

The presence of neutrophils in tumors has traditionally been considered to be indicative of a failed immune response against cancers. However, there is now evidence showing that neutrophils can promote tumor growth, and increasingly, the data support an active role for neutrophils in tumor progression to distant metastasis. Neutrophils have been implicated in promoting metastasis in cancer patients, where neutrophil numbers and neutrophil-related factors and functions have been associated with progressive disease. Nevertheless, the role of neutrophils in tumors, both at the primary and secondary sites, remains controversial, with some studies reporting their anti-tumor functions. This review will focus on the data demonstrating a role for neutrophils in both tumor growth and metastasis and will attempt to clarify the discrepancies in the literature.

Chemokines and cellular plasticity of ovarian cancer stem cells.

The diversity of cancer is generated through genetic alterations as well as by epigenetic events regulated by the tumor microenvironment. At the apex of this hierarchy are cancer stem cells (CSCs) which are characterized by their ability to self-renew, as well as to generate the cells constituting the tumor bulk. CSCs contribute to cancer metastasis and therapeutic resistance [1]. It is now clear that cellular interactions within the tumor microenvironment regulate both the cancer stem cell and bulk cell components which play an important role in tumor progression and metastasis. Deconvoluting the role of various components in the human cancer microenvironment and elucidating the mechanism of interaction has proved to be a great challenge. Recent studies have demonstrated that different immune components including Th22 cells [2] and myeloid derived suppressor cells (MDSCs) [3] are involved in the control of cancer stemness. Chemokines are important players in the immune responses. For some time it has been known that chemokines are able to target and recruit specific immune subsets into the microenvironment. For example, CXCL12 [4] and CXCL20 [5] mediate tumor trafficking of plasmacytoid dendritc cells (4) and regulatory T cells [5], respectively. These immune cell subsets can mediate immunosuppression and consequently promote cancer progression. Interestingly, chemokines may directly target tumor cells and affect tumorigenesis. CXCL8 (IL-8) [6] has been demonstrated to be involved in cancer stem cell biology and cancer cell metastasis. Furthering this work, Zhu et al, in this issue of Oncoscience, describe a new role for cancer stem cell-derived CCL5 in ovarian cancer metastasis. Ovarian cancer stem cells are enriched in cell fractions expressing CD133+ and ALDH-1+ [3, 7]. In an attempt to examine the role of CCL5 in cancer metastasis, Dr. Zhu and colleagues employed several complementary approaches to test the hypothesis that cancer stem cell-derived CCL5 played a role in endowing CSCs with invasive properties. They found that in the presence of CD133+ CSCs, CD133− cancer cells undergo an epithelial-mesenchymal transition (EMT)-like process and display enhanced metastatic capacity in in vitro assays as well as in vivo xenografts. They demonstrated that CD133+, but not CD133− cancer cells, expressed CCL5, with CCL5 signaling blockade abrogating and recombinant CCL5 mimicking these effects. In further support of the potential clinical significance of CCL5 and its receptors in tumorigenesis, they detected elevated expression of CCL5 and its receptors CCR1, CCR3 and CCR5 in human and murine metastatic epithelial ovarian carcinomas. To gain mechanistic insight into this process, they observed that paracrine CCL5 from CD133+ ovarian cancer stem cells activated the NF-κB signaling pathway in CD133− cells via binding CCR1, CCR3 and CCR5, thereby inducing EMT and tumor invasion. Therefore, it is reasonable to conclude that at least in this experimental setting, CCL5 and/or CCL5 expressing CSCs promote ovarian cancer EMT and potential metastasis. Although this manuscript represents a significant advance, many questions remain to be answered. The authors propose that CCL5 converts non-CSCs into CSCs through an EMT. However, they do not exclude the possibility that there are more than one form of CSCs in ovarian cancer since previous studies have suggested that CSCs can exist in alternative EMT- and MET-like states [8]. Thus, induction of EMT may represent transition in CSC state, rather than true induction of CSCs. In addition, the authors do not examine the role of other cell types in the tumor microenvironment which are capable of CCL5 expression. To what extent CD133+ cell-derived CCL5 is important in ovarian cancer metastasis in patients is not known. In addition, since these studies utilize established cell lines, it is unclear whether primary ovarian cells show similar cytokine expression patterns. Despite these limitations, this work adds to increasing evidence for the importance of CSCs and their regulation by cell-cell interactions in the tumor microenvironment. Furthermore, these studies suggest the possibility of inhibiting ovarian CSCs by blocking CCL5 signaling.

A novel embryonic plasticity gene signature that predicts metastatic competence and clinical outcome.

Currently, very few prognosticators accurately predict metastasis in cancer patients. In order to complete the metastatic cascade and successfully colonize distant sites, carcinoma cells undergo dynamic epithelial-mesenchymal-transition (EMT) and its reversal, mesenchymal-epithelial-transition (MET). While EMT-centric signatures correlate with response to therapy, they are unable to predict metastatic outcome. One reason is due to the wide range of transient phenotypes required for a tumor cell to disseminate and recreate a similar histology at distant sites. Since such dynamic cellular processes are also seen during embryo development (epithelial-like epiblast cells undergo transient EMT to generate the mesoderm, which eventually redifferentiates into epithelial tissues by MET), we sought to utilize this unique and highly conserved property of cellular plasticity to predict metastasis. Here we present the identification of a novel prognostic gene expression signature derived from mouse embryonic day 6.5 that is representative of extensive cellular plasticity, and predicts metastatic competence in human breast tumor cells. This signature may thus complement conventional clinical parameters to offer accurate prediction for outcome among multiple classes of breast cancer patients.

(15)O-Water PET Study of the Effect of Imatinib, a Selective Platelet-Derived Growth Factor Receptor Inhibitor, Versus Anakinra, an IL-1R Antagonist, on Water-Perfusable Tissue Fraction in Colorectal Cancer Metastases.

High interstitial fluid pressure (IFP) in colorectal cancer metastases may decrease the uptake and, thus, the effects of antitumor drugs. Imatinib, a selective inhibitor of platelet-derived growth factor receptors, and anakinra, an interleukin-1 receptor antagonist, respectively, increase drug uptake or decrease IFP in preclinical models of carcinoma. Drug-induced decrease in IFP in human metastases has not been objectively shown but should be reflected by an increase in water-perfusable tissue fraction (PTF) or tumor blood flow (TBF) using (15)O-water PET/CT and kinetic modeling. Hence, the aim of this study was to assess the effects of imatinib and anakinra on PTF and TBF in colorectal cancer metastases in patients. Nine patients with documented progressive disease despite all established therapy underwent (15)O-water PET/CT at baseline and at 2 d and 6-7 d after the start of oral administration of imatinib (400 mg/d). After a washout period of 1 wk, the protocol was repeated with anakinra (100 mg/d) subcutaneously. Six patients underwent a second baseline scan on the same day to assess reproducibility of PTF and TBF measurements. Volumes of interest were drawn over liver metastases and aorta. PTF and TBF were calculated using the standard single-tissue-compartment model. Imatinib administration during 6-7 d increased PTF from 0.62 ± 0.12 to 0.69 ± 0.13, compared with baseline and day 2 (P = 0.02, Wilcoxon test). No significant changes were found in TBF. PTF values were no longer significantly different from baseline 1 wk after the last imatinib dosage. Anakinra induced no significant change in PTF or TBF. The repeatability coefficients of PTF and TBF in liver lesions were 22% and 28%, respectively. Imatinib increases PTF of colorectal cancer metastases in patients and hence may increase the delivery of antitumor drugs. (15)O-water PET/CT and kinetic modeling provide insights into the microenvironment of human cancers.

Development of a bone targeted thermosensitive liposomal doxorubicin formulation based on a bisphosphonate modified non-ionic surfactant

Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10 min at 42 °C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42 °C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37 °C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis.