SciCombinator

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Concept: Neoplasm

171

Emodin has been showed to induce apoptosis of pancreatic cancer cells and inhibit tumor growth in our previous studies. This study was designed to investigate whether emodin could inhibit the angiogenesis of pancreatic cancer tissues and its mechanism.

Concepts: Cell cycle, Neoplasm, Metastasis, Pancreatic cancer, Apoptosis, Immune system, Oncology, Cancer

169

PURPOSE: Development of a heptamethine cyanine based tumor-targeting PET imaging probe for noninvasive detection and diagnosis of breast cancer. METHODS: Tumor-specific heptamethine-cyanine DOTA conjugate complexed with Cu-64 (PC-1001) was synthesized for breast cancer imaging. In vitro cellular uptake studies were performed in the breast cancer MCF-7 and noncancerous breast epithelial MCF-10A cell lines to establish tumor specificity. In vivo time-dependent fluorescence and PET imaging of breast tumor xenografts in mice were performed. Blood clearance, biodistribution, and tumor-specific uptake and plasma binding of PC-1001 were quantified. Tumor histology (H&E staining) and fluorescence imaging were examined. RESULTS: PC-1001 displayed similar fluorescence properties (ε=82,880cm(-1)M(-1), E(x)/E(m)=750/820nm) to the parental dye. Time-dependent cellular accumulation indicated significantly higher probe uptake (>2-fold, 30min) in MCF-7 than MCF-10A cells and the uptake was observed to be mediated by organic anion transport peptides (OATPs) system. In vivo studies revealed that PC-1001 has desirable accumulation profile in tumor tissues, with tumor versus muscle uptake of about 4.3 fold at 24h and 5.8 fold at 48h post probe injections. Blood half-life of PC-1001 was observed to be 4.3±0.2h. Microscopic fluorescence imaging of harvested tumor indicated that the uptake of PC-1001 was restricted to viable rather than necrotic tumor cells. CONCLUSIONS: A highly efficient tumor-targeting PET/fluorescence imaging probe PC-1001 is synthesized and validated in vitro in MCF-7 breast cancer cells and in vivo in mice breast cancer xenograft model.

Concepts: MCF-7, Tumor, Neoplasm, In vivo, Benign tumor, Oncology, Breast cancer, Cancer

167

BACKGROUND: New therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies. METHODS: We explored the combination of ABT-737 and chloroquine, an inhibitor of autophagy, in preclinical models of SCLC. These included cell culture analyses of viability and of autophagic and apoptotic pathway induction, as well as in vivo analyses of efficacy in multiple xenograft models. RESULTS: Combination treatment of SCLC lines with ABT-737 and chloroquine decreased viability and increased caspase-3 activation over treatment with either single agent. ABT-737 induced several hallmarks of autophagy. However, knockdown of beclin-1, a key regulator of entry into autophagy, diminished the efficacy of ABT-737, suggesting either that the effects of chloroquine were nonspecific or that induction but not completion of autophagy is necessary for the combined effect of ABT-737 and chloroquine. ABT-737 and chloroquine in SCLC cell lines downregulated Mcl-1 and upregulated NOXA, both of which may promote apoptosis. Treatment of tumor-bearing mice demonstrated that chloroquine could enhance ABT-737-mediated tumor growth inhibition against NCI-H209 xenografts, but did not alter ABT-737 response in three primary patient-derived xenograft models. CONCLUSION: These data suggest that although ABT-737 can induce autophagy in SCLC, autophagic inhibition by choroquine does not markedly alter in vivo response to ABT-737 in relevant preclinical models, arguing against this as a treatment strategy for SCLC.

Concepts: Cell, Tumor, Neoplasm, Small cell carcinoma, Oncology, Apoptosis, Lung cancer, Cancer

167

In recent studies, both tumor morphology and vascularity played an important role in differentiating breast tumors. In this article, a computer-aided diagnosis (CAD) system was proposed to quantify the tumor morphology of vascularity on three-dimensional (3-D) power Doppler breast ultrasound (PDUS) images. We segmented the tumor margin by the level set method and skeletonized vessels by the 3-D thinning algorithm from 3-D PDUS data to capture the B-mode and vascularity features. The B-mode features including texture, shape and ellipsoid fitting and the vascularity features containing volume, complexity, length, radius and tortuosity were used to differentiate breast tumors. In the experiment, 82 biopsy-verified lesions including 41 benign and 41 malignant lesions were used to test the performance of the proposed system. The proposed method performed well, achieving accuracy, sensitivity, specificity and Az values of 85.37% (70/82), 85.37% (35/41), 85.37% (35/41) and 0.9104, respectively.

Concepts: Brain tumor, Neoplasm, Tumor, Breast cancer, Level set method, Benign tumor, Oncology, Cancer

165

The inherently toxic nature of chemotherapy drugs is essential for them to kill cancer cells but is also the source of the detrimental side effects experienced by patients. One strategy to reduce these side effects is to limit the healthy tissue exposure by encapsulating the drugs in a vehicle that demonstrates a very low leak rate in circulation while simultaneously having the potential for rapid release once inside the tumor. Designing a vehicle with these two opposing properties is the major challenge in the field of drug delivery. A triggering event is required to change the vehicle from its stable circulating state to its unstable release state. A unique mechanical actuation type trigger is possible by harnessing the size changes that occur when microbubbles interact with ultrasound. These mechanical actuations can burst liposomes and cell membranes alike allowing for rapid drug release and facilitating delivery into nearby cells. The tight focusing ability of the ultrasound to just a few cubic millimeters allows for precise control over the tissue location where the microbubbles destabilize the vehicles. This allows the ultrasound to highlight the tumor tissue and cause rapid drug release from any carrier present. Different vehicle designs have been demonstrated from carrying drug on just the surface of the microbubble itself to encapsulating the microbubble along with the drug within a liposome. In the future, nanoparticles may extend the circulation half-life of these ultrasound triggerable drug-delivery vehicles by acting as nucleation sites of ultrasound-induced mechanical actuation. In addition to the drug delivery capability, the microbubble size changes can also be used to create imaging contrast agents that could allow the internal chemical environment of a tumor to be studied to help improve the diagnosis and detection of cancer. The ability to attain truly tumor-specific release from circulating drug-delivery vehicles is an exciting future prospect to reduce chemotherapy side effects while increasing drug effectiveness.

Concepts: Cell membrane, Neoplasm, Doxorubicin, Experimental cancer treatment, Chemotherapy, Immune system, Oncology, Cancer

148

Collectively, lymphoid neoplasms are the fourth most common cancer and the sixth leading cause of cancer death in the United States. The authors provide contemporary lymphoid neoplasm statistics by subtype based on the 2008 World Health Organization classifications, including the most current US incidence and survival data. Presented for the first time are estimates of the total numbers of US lymphoid neoplasm cases by subtype as well as a detailed evaluation of incidence and survival statistics. In 2016, 136,960 new lymphoid neoplasms are expected. Overall lymphoma incidence rates have declined in recent years, but trends vary by subtype. Precursor lymphoid neoplasm incidence rates increased from 2001 to 2012, particularly for B-cell neoplasms. Among the mature lymphoid neoplasms, the fastest increase was for plasma cell neoplasms. Rates also increased for mantle cell lymphoma (males), marginal zone lymphoma, hairy cell leukemia, and mycosis fungoides. Like incidence, survival for both mature T-cell lymphomas and mature B-cell lymphomas varied by subtype and by race. Patients with peripheral T-cell lymphomas had among the worst 5-year relative survival (36%-56%, depending on race/sex), while those with mycosis fungoides had among the best survival (79%-92%). For B-cell lymphomas, 5-year survival ranged from 83% to 91% for patients with marginal zone lymphoma and from 78% to 92% for those with hairy cell leukemia; but the rates were as low as 47% to 63% for patients with Burkitt lymphoma and 44% to 48% for those with plasma cell neoplasms. In general, black men had the lowest survival across lymphoid malignancy subtypes. These contemporary incidence and survival statistics are useful for developing management strategies for these cancers and can offer clues regarding their etiology. CA Cancer J Clin 2016. © 2016 American Cancer Society.

Concepts: Neoplasm, Leukemia, B cell, AIDS, Lymphoma, Oncology, Types of cancer, Cancer

147

Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth.

Concepts: Gene expression, Benign tumor, Immune system, Colorectal cancer, Neoplasm, Oncology, Tumor, Cancer

145

Myopericytoma is a soft tissue tumor with perivascular myoid differentiation. It accounts for 1% of the vascular tumors and involves mostly cutaneous or subcutaneous tissue of the limbs in adults. Malignant myopericytoma is exceedingly rare. A 15-year old girl presented with slowly progressive mass over left shoulder region. Histopathology and immunohistochemistry after complete excision revealed it as malignant myopericytoma.

Concepts: Neoplasm, Soft tissue sarcoma, Dermis, Tissue, Histology, Oncology, Cancer, Anatomical pathology

142

Chimeric antigen receptor T (CAR-T) cells have shown promising efficacy in treatment of hematological malignancies, but its applications in solid tumors need further exploration. In this study, we investigated CAR-T therapy targeting carcino-embryonic antigen (CEA)-positive colorectal cancer (CRC) patients with metastases to evaluate its safety and efficacy. Five escalating dose levels (DLs) (1 × 10(5) to 1 × 10(8)/CAR(+)/kg cells) of CAR-T were applied in 10 CRC patients. Our data showed that severe adverse events related to CAR-T therapy were not observed. Of the 10 patients, 7 patients who experienced progressive disease (PD) in previous treatments had stable disease after CAR-T therapy. Two patients remained with stable disease for more than 30 weeks, and two patients showed tumor shrinkage by positron emission tomography (PET)/computed tomography (CT) and MRI analysis, respectively. Decline of serum CEA level was apparent in most patients even in long-term observation. Furthermore, we observed persistence of CAR-T cells in peripheral blood of patients receiving high doses of CAR-T therapy. Importantly, we observed CAR-T cell proliferation especially in patients after a second CAR-T therapy. Taken together, we demonstrated that CEA CAR-T cell therapy was well tolerated in CEA(+) CRC patients even in high doses, and some efficacy was observed in most of the treated patients.

Concepts: Positron emission tomography, Neoplasm, Colorectal cancer, Lung cancer, Tumor, Protein, Oncology, Cancer

140

Obesity is involved in tumor progression. However, the corresponding mechanisms remain largely unknown. Here, we report that adipocytes increase the invasive ability of tumor cells by producing exosomes with a high level of MMP3. Compared with 3T3-L1 cells, 3T3-L1 adipocytes are enriched in MMP3 protein and can transfer MMP3 to 3LL lung cancer cells. Then, MMP3 activates MMP9 activity in 3LL cells and promotes invasion in vitro and in vivo via MMP9. Furthermore, MMP3 protein levels in lung tumor tissues from obese patients are increased compared with those of non-obese patients. In addition, MMP3 protein levels are positively correlated with MMP9 activity in tumor tissues. Therefore, our results reveal a novel mechanism in the adipocyte-derived exosome-mediated promotion of lung tumor metastasis, which extends our knowledge regarding obesity and tumor progression.

Concepts: Neoplasm, Breast cancer, Obesity, Prostate cancer, Oncology, Metastasis, Lung cancer, Cancer