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Tumor metastasis is responsible for chemotherapeutic failure and cancer-related death. Moreover, circulating tumor cell (CTC) clusters play a pivotal role in tumor metastasis. Herein, we develop cancer-specific calcium nanoregulators to suppress the generation and circulation of CTC clusters by cancer membrane-coated digoxin (DIG) and doxorubicin (DOX) co-encapsulated PLGA nanoparticles (CPDDs). CPDDs could precisely target the homologous primary tumor cells and CTC clusters in blood and lymphatic circulation. Intriguingly, CPDDs induce the accumulation of intracellular Ca2+ by inhibiting Na+/K+-ATPase, which help restrain cell–cell junctions to disaggregate CTC clusters. Meanwhile, CPDDs suppress the epithelial–mesenchymal transition (EMT) process, resulting in inhibiting tumor cells escape from the primary site. Moreover, the combination of DOX and DIG at a mass ratio of 5:1 synergistically induces the apoptosis of tumor cells. In vitro and in vivo results demonstrate that CPDDs not only effectively inhibit the generation and circulation of CTC clusters, but also precisely target and eliminate primary tumors. Our findings present a novel approach for anti-metastasis combinational chemotherapy., Graphical abstract Cancer-specific calcium nanoregulator was developed to enhance anti-metastasis combinational chemotherapy, which showed remarkable anti-tumor and anti-metastasis efficacy by targeting the homologous tumor cells, restraining the epithelial–mesenchymal transition, dissociating and depleting circulating tumor cell clusters.Image 1

Highlights • CTCs can be reliably captured with a microfluidic disc in unresectable PDAC patients. • EpCAM/CK and additional Plectin-1 can effectively identify PDAC CTCs. • Decreased number of CTCs after chemotherapy is associated with longer survival. • The relative change of CTCs after chemotherapy can be a surrogate marker for survival., Circulating tumor cells (CTCs) have emerged as liquid biopsy biomarker providing non-invasive assessment of cancer progression and biology. We investigated whether longitudinal analysis of CTCs could monitor disease progression, response to chemotherapy, and survival in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). A total of 52 patients with PDAC were prospectively enrolled in this study. Peripheral blood samples were serially collected at the time of diagnosis and after chemotherapy with clinical assessments. CTCs were isolated through a centrifugal microfluidic disc, enumerated with immunostaining against Epithelial cell adhesion molecule (EpCAM), Cytokeratin (CK), Plectin-1 and CD45, and identified by an automated imaging system. One or more CTCs were detected in 84.62% patients with unresectable PDAC at the time of diagnosis. CTC numbers were not statistically different across tumor sizes, location and metastatic sites. The absolute number of CTCs after chemotherapy was inversely related to overall survival (OS), and the decreased number of CTCs after chemotherapy was significantly associated with longer OS in patients with PDAC. Identifying CTCs and monitoring CTC changes after chemotherapy could be a useful prognostic marker for survival in patients with unresectable PDACs.

Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies. In oral squamous cell carcinoma (OSCC), αv integrin is a crucial mediator of multicellular clustering and collective movement in vitro; however, its contribution to metastatic spread remains to be addressed. According to the emerging therapeutic concept, dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas. This study aimed to investigate the anti-OSCC potential of novel endostatin-derived polypeptide PEP06 as a cluster-dissociating therapeutic agent in vitro. Firstly, we found marked enrichment of αv integrin in collectively invading multicellular clusters in human OSCCs. Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of αv integrin in cancerous lesions. Following PEP06 treatment, cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC were significantly inhibited. Moreover, PEP06 suppressed αv integrin/FAK/Src signaling in OSCC cells. PEP06-induced loss of active Src and E-cadherin from cell–cell contacts contributed to diminished collective migration of OSCC in vitro. Overall, these results suggest that PEP06 polypeptide 30 inhibiting αv integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent., Graphical abstract PEP06 polypeptide 30, acting as a cluster-dissociating therapeutic agent, possesses the effect of anti-metastatic potential in oral squamous cell carcinoma by inhibiting αv integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions.Image 1

Background Osteosarcoma (OS) is the most common primary bone tumor and the third leading cause of pediatric cancer deaths. Liquid biopsies are an alternative to current diagnostic imaging modalities that can be used to monitor treatment efficacy and the development of metastases. This study addresses the use of novel biomarkers to detect circulating osteosarcoma cells. Procedures Flow cytometry was used to evaluate the relative expression of epithelial cell adhesion molecule (EpCAM), ganglioside 2 and 3 (GD2/3), and cell surface vimentin (CSV) on a panel of OS cell lines. A microfluidic device was used to affirm the efficacy of GD2/3 and CSV to capture CTCs. Once captured, CTCs on the device are enumerated and the capture efficiency for each marker is measured. Patient samples were captured using the LFAM chip. Results We report the evaluation of GD2, GD3, and CSV as markers for OS cell capture in cell lines and in patient samples. The results of our capture studies correlate with our flow cytometry data and have shown a low capture efficiency of OS cells using EpCAM antibodies, while showing a moderate capture efficiency of OS cells using the GD2, GD3, and CSV antibodies independently. The combination of biomarkers demonstrate a high capture efficiency of approximately 80%. This is further supported by the detection of 1–1.5 CTCs per mL of blood using GD2 + CSV in OS patient samples. Conclusions The combination of GD2 + CSV significantly increased the capture efficacy of OS cells. The detection of CTCs through routine blood sampling may be used clinically for earlier detection of metastases and monitoring the therapeutic effect of treatments in metastatic osteosarcomas.

Highlights • A high platelet-to-lymphocyte ratio (PLR; >124) before curative surgical resection was found to be associated with reduced disease-free survival (DFS) in non-metastatic colon cancer patients. • A high PLR was predominant among patients with circulating tumor microemboli (CTM). • This prospective study revealed a mechanism of interaction between circulating tumor cells (CTCs) and other blood components, and implicated platelets in CTC survival. • The present findings support the use of blood biomarkers to better identify and follow high-risk colon cancer patients., Colorectal cancer is a common and often deadly cancer. Circulating tumor cells (CTCs) have been implicated as a potentially valuable prognosis factor. The detection of circulating tumor microemboli (CTM) and of simple blood component parameters that reflect inflammatory status, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), may provide information about tumor progression. The aim of this study was to explore the importance of CTCs, CTM, PLR, and NLR prospectively in non-metastatic colon cancer progression. CTCs were enriched using ISETⓇ (Isolation by SizE of Tumor cells) and identified by immunocytochemical exclusion of leukocytes. We evaluated CTCs and blood cell parameters in a cohort of 69 stage I–III colon cancer patients (52.2% men; median age, 61 years; age range, 19–87 years) at a baseline timepoint prior to resection surgery. The median of CTC levels at baseline was 20 cells/8 mL (0–94) and higher levels were associated with CTM presence (p = 0.02). CTM were found in 18 (26.1%) patients. Of 18 stage I patients, 33.3% had CTM and of 51 stages II or III patients, 13.7% had CTM (p = 0.08). Patients with a high PLR (>124) were mostly (75.6%) diagnosed with high-risk stages II/III cancer (stages I/low-risk II, 24.4%; p = 0.014). All 8 patients that had disease recurrence during follow-up had a high PLR (p = 0.02 vs. low PLR). NLR was not significantly associated with disease stage or recurrence. The present results indicate that CTCs and PLR analyses may be clinically useful for colon cancer management and risk stratification.

Gastrointestinal cancers account for more cancer-related deaths than any other organ system, owing in part to difficulties in early detection, treatment response assessment, and post-treatment surveillance. Circulating biomarkers hold the promise for noninvasive liquid biopsy platforms to overcome these obstacles. Although tumors shed detectable levels of degraded genetic material and cellular debris into peripheral blood, identifying reproducible and clinically relevant information from these analytes (eg, cell-free nucleotides, exosomes, proteins) has proven difficult. Cell-based circulating biomarkers also present challenges, but have multiple advantages including allowing for a more comprehensive tumor analysis, and communicating the risk of metastatic spread. Circulating tumor cells have dominated the cancer cell biomarker field with robust evidence in extraintestinal cancers; however, establishing their clinical utility beyond that of prognostication in colorectal and pancreatic cancers has remained elusive. Recently identified novel populations of tumor-derived cells bring renewed potential to this area of investigation. Cancer-associated macrophage-like cells, immune cells with phagocytosed tumor material, also show utility in prognostication and assessing treatment responsiveness. In addition, circulating hybrid cells are the result of tumor–macrophage fusion, with mounting evidence for a role in the metastatic cascade. Because of their relative abundance in circulation, circulating hybrid cells have great potential as a liquid biomarker for early detection, prognostication, and surveillance. In all, the power of the cell reaches beyond enumeration by providing a cellular source of tumor DNA, RNA, and protein, which can be harnessed to impact overall survival. Keywords: Fusion Hybrid, CAML, CHC, Liquid Biopsy, Macrophage

There have been many recent exciting developments in biomimetic nanoparticles for biomedical applications. Inflammation, a protective response involving immune cells, blood vessels, and molecular mediators directed against harmful stimuli, is closely associated with many human diseases. As a result, biomimetic nanoparticles mimicking immune cells can help achieve molecular imaging and precise drug delivery to these inflammatory sites. This review is focused on inflammation-targeting biomimetic nanoparticles and will provide an in-depth look at the design of these nanoparticles to maximize their benefits for disease diagnosis and treatment., Graphical abstract This review talks about basic strategies of inflammation-targeting biomimetic nanoparticles, which includes i) synthetic nanoparticles modified with targeting ligands that mimic cell surface proteins; ii) cell membrane-coated nanoparticles; iii) liposomes engineered with cell membrane proteins.fx1

Various types of circulating tumor cell (CTC) detection systems have recently been developed that show a high CTC detection rate. However, it is a big challenge to find a system that can provide better prognostic value than CellSearch in head-to-head comparison. We have developed a novel semi-automated CTC enumeration system (fluidic cell microarray chip system, FCMC) that captures CTC independently of tumor-specific markers or physical properties. Here, we compared the CTC detection sensitivity and the prognostic value of FCMC with CellSearch in breast cancer patients. FCMC was validated in preclinical studies using spike-in samples and in blood samples from 20 healthy donors and 22 breast cancer patients in this study. Using spike-in samples, a statistically higher detection rate (p = 0.010) of MDA-MB-231 cells and an equivalent detection rate (p = 0.497) of MCF-7 cells were obtained with FCMC in comparison with CellSearch. The number of CTC detected in samples from patients that was above a threshold value as determined from healthy donors was evaluated. The CTC number detected using FCMC was significantly higher than that using CellSearch (p = 0.00037). CTC numbers obtained using either FCMC or CellSearch had prognostic value, as assessed by progression free survival. The hazard ratio between CTC + and CTC − was 4.229 in CellSearch (95% CI, 1.31 to 13.66; p = 0.01591); in contrast, it was 11.31 in FCMC (95% CI, 2.245 to 57.0; p = 0.000244). CTC detected using FCMC, like the CTC detected using CellSearch, have the potential to be a strong prognostic factor for cancer patients.