clay and Neoplasm-Metastasis

Calcium aluminosilicate clay (CASAD) is a naturally occurring clay that serves as a cation exchange absorbent. We hypothesized that oral administration of CASAD would reduce the rate of grade 3/4 diarrhea associated with irinotecan use for metastatic colorectal cancer (CRC) by adsorbing the SN-38 metabolite.. Patients receiving irinotecan-based chemotherapy were randomized equally between CASAD and placebo arms in this multicenter trial in order to assess differences in the proportions of patients with grade 3/4 diarrhea within 6 weeks. Additionally, we compared symptom severity between the two arms using the M.D. Anderson Symptom Inventory.. Between May 2009 and May 2012, 100 patients were enrolled. In evaluable patients, 7 of 43 (16 %) on the CASAD arm compared to 3 of 32 (9 %) on the placebo arm experienced grade 3/4 diarrhea (P = 0.70). The rate of any diarrhea among all patients was similar (CASAD arm, 64 % vs. placebo arm, 70 %). The rate of study dropout was 14 % in the CASAD arm and 38 % in the placebo arm (P = 0.01). No differences were found in symptom severity, individual symptom items, and in serious adverse events between the two arms.. Compared to placebo, CASAD use was safe but ineffective in preventing diarrhea in metastatic CRC patients treated with irinotecan-containing chemotherapy regimens. There were no distinct signals in terms of patient symptoms between arms, but there was significantly more patient dropout in the placebo arm. Future CASAD trials will focus on the active treatment of diarrhea.

Topics: Adult; Aged; Aged, 80 and over; Aluminum Silicates; Antineoplastic Agents, Phytogenic; Camptothecin; Clay; Colorectal Neoplasms; Diarrhea; Double-Blind Method; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Placebos; Treatment Outcome; Young Adult

Cancer recurrence and metastasis are worldwide challenges but current bimodular strategies such as combined radiotherapy and chemotherapy (CTX), and photothermal therapy (PTT) and immunotherapy have succeeded only in some limited cases. Thus in the present study, a multifunctional nanomedicine has been rationally designed via elegantly integrating three FDA-approved therapeutics, that is, indocyanine green (for PTT), doxorubicin (for CTX), and CpG (for immunotherapy) into the structure of layered double hydroxide (LDH) nanoparticles, aiming to completely prevent the recurrence and metastasis of invasive breast cancer. This multifunctional hybrid nanomedicine has been demonstrated to eliminate the primary tumor and efficiently prevent tumor recurrence and lung metastasis through combined PTT/CTX and induction of specific and strong immune responses mediated by the hybrid nanomedicine in a 4T1 breast cancer mouse model. Furthermore, the promoted in situ immunity has significantly inhibited the growth of reinoculated distant tumors. Altogether, our multifunctional LDH-based nanomedicine has showed an excellent efficacy in invasive cancer treatment using much lower doses of three FDA-approved therapeutics, providing a preclinical/clinical alternative to cost-effectively treat invasive breast cancer.

Topics: Animals; Breast Neoplasms; Clay; Female; Humans; Lung Neoplasms; MCF-7 Cells; Mice; Mice, Inbred BALB C; Nanomedicine; Nanoparticles; Neoplasm Invasiveness; Neoplasm Metastasis; Xenograft Model Antitumor Assays

Breast cancer (BrCa) preferentially spreads to bone and colonises within the bone marrow to cause bone metastases. To improve the outcome of patients with BrCa bone metastasis, we need to understand better the mechanisms underlying bone metastasis. Researchers have relied heavily upon in vivo xenografts due to limited availability of human bone metastasis samples. A significant limitation of these is that they do not have a human bone microenvironment. To address this issue, we have developed a nanoclay-based 3D in vitro model of BrCa bone metastasis using human mesenchymal stem cells (MSCs) and human BrCa cells mimicking late stage of BrCa pathogenesis at the metastatic site. This 3D model can provide a microenvironment suitable for cell-cell and cell-matrix interactions whilst retaining the behaviour of BrCa cells with different metastasis potential (i.e., highly metastatic MDA-MB-231 and low metastatic MCF-7) as shown by the production of alkaline phosphatase and matrix metalloproteinase-9. The sequential culture of MSCs with MCF-7 exhibited 3D tumouroids formation and also occurrence of mesenchymal to epithelial transition of cancer metastasis as evidenced by gene expression and immunocytochemistry. The unique and distinct behaviour of highly metastatic MDA-MB-231 and the low metastatic MCF-7 was observed at the bone metastasis site. The changes to migratory capabilities and invasiveness in MDA-MB-231 in comparison with tumour growth with MCF-7 was observed. Together, a novel bone-mimetic 3D in vitro BrCa model has been developed that could be used to study mechanisms governing the later stage of cancer pathogenesis in bone.

Topics: Bone Neoplasms; Breast Neoplasms; Cell Culture Techniques; Clay; Female; Humans; MCF-7 Cells; Models, Biological; Nanostructures; Neoplasm Metastasis; Tissue Engineering

Cancer metastasis results from the suppression of adhesion between cancer cells and the extracellular matrix, causing their migration from the primary tumor location and the subsequent formation of tumors in distant organs. This study demonstrates the potential use of nano-sized clay mineral particles to modulate adhesions between tumor cells and with the surrounding extracellular matrix. Atomic force microscopy studies of live cell cultures reveal a significant increase in adhesion between tumor cells and their environment after treatment with different types of electrically charged clay nanoparticles. The enhancement of adhesion among cancer cells was further confirmed through scratch type of wound healing assay studies. To provide insight into the adhesion mechanisms introduced by the clay nanoparticles, we performed a molecular-level computer simulation of cell adhesions in the presence and absence of the nanoparticles. Strong van der Waals and electrostatic attractions modelled in the molecular simulations result in an increase in the cohesive energy density of these environments when treated with clay crystallites. The increase in the cohesive energy density after the sorption of clay crystallites on cell-cell and cell-extracellular matrix complexes lends weight to our strategy of using clay nanoparticles for the restoration of adhesion among cancer cells and prevention of metastasis.

Topics: Aluminum Silicates; Cell Adhesion; Clay; Computer Simulation; Extracellular Matrix; Humans; Nanoparticles; Neoplasm Metastasis; Neoplasms; Tumor Cells, Cultured

Nanocomposite scaffolds show extensive applications in regenerative medicine and have shown promise as in vitro analogues of human tissue that can be used for the study of diseases. The complex nature of cancer metastasis is recently investigated using several 3D scaffold models. Herein, we report a polymer-nanoclay-based in vitro tumour model that recapitulates early stage of prostate cancer (PCa) colonization during skeletal metastasis on bone mimetic scaffolds. A unique cell culture system termed as "sequential culture (SC)" has been applied to create a bone-mimetic niche for colonization of PCa cells. Human mesenchymal stem cells (MSCs) were seeded on the bone-mimetic scaffolds, where they differentiated into bone cells and then formed mineralized bone matrix without osteogenic supplements. Further, PCa was seeded on MSCs-seeded scaffolds. Sequentially cultured PCa cells with MSCs formed self-organized multicellular tumoroids with distinct tight cellular junctions and hypoxic core regions. Extensive quantitative reverse transcription-polymerase chain reaction experiments were performed to evaluate the expressions of genes related to osteotropic bone metastasis of PCa. On the nanoclay scaffolds, the MSCs differentiated to mature osteoblasts and epithelial to mesenchymal transition was inhibited whereas mesenchymal to epithelial transition was enhanced, as also the hypoxia increased angiogenesis, and finally, PCa cells initiated osteoblastic lesion. Further, the SC technique has significant effects on expression of key metastasis-related genes. Therefore, the SC-based tumour model can be applied to recapitulate more consistent osteotropic cancer cell behavior in understanding tumour biology. This model also can be implemented for drug screening to target colonization stage of PCa cells in the bone microenvironment.

Topics: Biomimetic Materials; Cell Differentiation; Cell Hypoxia; Cell Line, Tumor; Cell Shape; Clay; Core Binding Factor Alpha 1 Subunit; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Male; Mesenchymal Stem Cells; Nanoparticles; Neoplasm Metastasis; Neovascularization, Pathologic; Osteoblasts; Osteogenesis; Prostate-Specific Antigen; Prostatic Neoplasms; Spheroids, Cellular; Tissue Scaffolds

The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion.

Topics: Aluminum Silicates; Biocompatible Materials; Biomarkers; Blood Cells; Cell Adhesion; Cell Line, Tumor; Cell Separation; Clay; Humans; Leukocytes; Ligands; MCF-7 Cells; Nanotubes; Neoplasm Metastasis; Neoplastic Cells, Circulating; Neutrophils; Prognosis; Quaternary Ammonium Compounds; Selectins; Surface-Active Agents

Circulating tumor cells (CTCs) can be used clinically to treat cancer. As a diagnostic tool, the CTC count can be used to follow disease progression, and as a treatment tool, CTCs can be used to rapidly develop personalized therapeutic strategies. To be effectively used, however, CTCs must be isolated at high purity without inflicting cellular damage.. We designed a microscale flow device with a functionalized surface of E-selectin and antibody molecules against epithelial markers. The device was additionally enhanced with a halloysite nanotube coating. We created model samples in which a known number of labeled cancer cells were suspended in healthy whole blood to determine device capture efficiency. We then isolated and cultured primary CTCs from buffy coat samples of patients diagnosed with metastatic cancer.. Approximately 50% of CTCs were captured from model samples. Samples from 12 metastatic cancer patients and 8 healthy participants were processed in nanotube-coated or smooth devices to isolate CTCs. We isolated 20-704 viable CTCs per 3.75-mL sample, achieving purities of 18%-80% CTCs. The nanotube-coated surface significantly improved capture purities (P = 0.0004). Experiments suggested that this increase in purity was due to suppression of leukocyte spreading.. The device successfully isolates viable CTCs from both blood and buffy coat samples. The approximately 50% capture rate with purities >50% with the nanotube coating demonstrates the functionality of this device in a clinical setting and opens the door for personalized cancer therapies.

Topics: Aluminum Silicates; Antibodies; Antigens, Neoplasm; Antigens, Surface; Blood Buffy Coat; Breast Neoplasms; Cell Adhesion; Cell Adhesion Molecules; Cell Count; Cell Separation; Clay; E-Selectin; Epithelial Cell Adhesion Molecule; Female; Glutamate Carboxypeptidase II; Humans; Leukocytes; Lung Neoplasms; Male; Nanotubes; Neoplasm Metastasis; Neoplastic Cells, Circulating; Ovarian Neoplasms; Polyurethanes; Prostatic Neoplasms