The CaSm (LSm1) oncogene promotes transformation, chemoresistance and metastasis of pancreatic cancer cells.

The cancer-associated Sm-like (CaSm) oncogene is overexpressed in 87% of human pancreatic tumor samples and CaSm knockdown has demonstrated therapeutic efficacy in murine models of pancreatic cancer. Evidence indicates that CaSm modulates messenger RNA degradation; however, its target genes and the mechanisms by which CaSm promotes pancreatic cancer remain largely unknown. Here, we demonstrate that the CaSm overexpression alters several hallmarks of cancer-including transformation, proliferation, chemoresistance and metastasis. Doxycycline-induced CaSm expression enhanced proliferation and both anchorage-dependent and -independent growth of the human Panc-1 cells in vitro. CaSm induction decreased gemcitabine-induced cytotoxicity and altered the expression of apoptotic regulation genes, including Bad, E2F1 and Bcl-XL. CaSm-overexpressing Panc-1 cells were twofold more migratory and fourfold more invasive than the driver controls and demonstrated characteristics of epithelial-to-mesenchymal transition such as morphological changes and decreased E-cadherin expression. CaSm induction resulted in changes in RNA expression of metastasis-associated genes such as MMP1, SerpinB5, uPAR and Slug. Using a murine model of metastatic pancreatic cancer, injection of CaSm-induced Panc-1 cells resulted in a higher abundance of hepatic metastatic lesions. Overall, CaSm overexpression contributed to a more aggressive cancer phenotype in Panc-1 cells, further supporting the use of CaSm as a therapeutic target against pancreatic cancer.

Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer.

Although mortality from colorectal cancer (CRC) is decreasing, CRC is still the second highest cause of cancer-related deaths in America. Chemotherapy and radiation therapy now have central roles in our strategies to fight cancer, although we continue to lack novel strategies overcoming therapeutic resistance. Molecular mechanisms of therapeutic resistance in CRC continue to be under intense investigation. In this review, we highlight the recent evidence linking epithelial-to-mesenchymal transition (EMT) with aggressive tumor biology as well as with the cancer stem cells (CSCs) across multiple organ systems including colon cancer. Furthermore, in the era of neo-adjuvant treatment, the clinical implications are concerning that our treatments may have the potential to induce more aggressive cancer cells through EMT, perhaps even generating CSCs more capable of metastasis and further resistant to treatment. This concern and potential reality highlights the critical need for further understanding the impact of clinical therapy on the pathobiology of cancer and further supports the need to therapeutically target the CSC. Besides serving as potential biomarkers for aggressive tumor biology and therapeutic resistance, EMT and CSC molecular pathways may highlight novel therapeutic targets as strategies for improving the response to conventional anti-neoplastic agents translating into improved oncologic outcomes.

Transferrin receptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer to gemcitabine therapy.

To overcome gene therapy barriers such as low transfection efficiency and nonspecific delivery, liposomal nanoparticles targeted by a single-chain antibody fragment to the transferrin receptor (TfRscFv) delivering wild-type (wt) human p53 (SGT-53) were developed for tumor-specific targeting. We hypothesize that SGT-53 in combination with gemcitabine will demonstrate enhanced therapeutic benefit in an in vivo metastatic pancreatic cancer model. Intrasplenic injection of 1 × 10(6) Panc02 murine pancreatic cancer cells was used to generate in vivo hepatic metastatic tumors. Nanoparticle localization was assessed by tail vein injection of TfRscFv with fluorescently labeled oligonucleotides (6-carboxyfluorescein phosphoramidite (6FAM) ODN) imaged by Xenogen IVIS 200 scan. SGT-53 (equivalent to 30 µg of p53 intravenously) and gemcitabine (20 mg/kg intraperitoneally) alone and in combination were administered biweekly and compared with untreated mice. Survival was determined by blinded daily assessment of morbidity. Human wtp53 expression and transferrin levels in the tumors were assessed by western blot analysis. Tumor burden was quantified by liver weight. Xenogen imaging demonstrated tumor-specific uptake of TfRscFv-6FAM ODN. Exogenous human wtp53 protein was detected in the SGT-53-treated tumors compared with control. Compared with untreated mice with metastatic tumors demonstrating median survival of 20 days, SGT-53, gemcitabine and the combination demonstrated improved median survival of 29, 30 and 37 days, respectively. The combination treatment prolonged median survival when compared with single drug treatment and decreased tumor burden. The tumor targeting liposomal-based SGT-53 nanoparticle is capable of sensitizing pancreatic cancer to conventional chemotherapy in pancreatic cancer models. This approach has the potential to be translated into a new, more effective therapy for pancreatic cancer. Further optimization is ongoing, moving towards a Phase 1B/2 clinical trial.

Management of bevacizumab-associated bowel perforation: a case series and review of the literature.

BACKGROUND: This study examined the various approaches to the management of perforation and the associated outcomes in patients with bevacizumab-associated bowel perforation at a tertiary cancer center. PATIENTS AND METHODS: Our institutional pharmacy database was searched to identify all patients who had received bevacizumab over a 2-year period (January 2004 to October 2006). Medical records of these patients were examined for reports of confirmed bowel perforation or fistula, associated clinicopathological factors, treatment, and outcomes. RESULTS: We identified 1442 patients who had been treated with bevacizumab over the study period with perforation occurring in 24 (1.7%). The breakdown of these 24 patients by disease site was as follows: ovarian (3 of 50, 6%), gastroesophageal (2 of 38, 5.3%), pancreatic (7 of 141, 5%), unknown primary (1 of 60, 1.7%), lung (1 of 67, 1.5%), colorectal (6 of 478, 1.3%), and renal cell (4 of 269, 1.5%). The majority of patients (n = 19, 79%) were initially managed nonoperatively. Only five (21%) patients ultimately underwent surgical exploration, with a subsequent anastomotic leak developing in one patient. The overall 30-day mortality rate was 12.5%. CONCLUSIONS: Bevacizumab-associated bowel perforation occurs in patients with various malignancies, with an incidence of 1.7%. Nonoperative treatment is a viable approach to management in selected patients.

The hottest sentinel lymph node is not always the positive node.

The technique of identifying the sentinel lymph node (SLN) varies from each individual institution. Generally, the highest isotope count in a lymph node is considered the SLN, whereas other radioactive nodes might also be removed. The purpose of our study was to determine if the hottest node was always the tumor-containing node. Two hundred forty-seven breast cancer patients underwent SLN biopsy from April 1998 to April 2002. Lymphatic mapping involved a radiocolloid injection and lymphoscintigraphy followed by intraoperative assessment with a hand-held gamma probe. All SLN(s) with radioactive counts 10 per cent or more of the ex vivo counts of the most radioactive SLN were removed. The SLN were sliced at 2-mm intervals with 4-microm step-sections (92-microm spacing) and evaluated by microscopy and immunohistochemistry. One hundred twenty (49%) of the 247 patients had 2 or more nodes resected. Of these 120 patients, 33 (28%) had a tumor-bearing node. In 25 (74%) cases, the tumor-bearing node was the most radioactive; however, in 8 (26%) cases, the positive node was a lesser reactive node. Although the most radioactive node in a draining basin is considered the SLN, this is often not the metastatic node. Therefore, all nodes with significant radioactive counts must be removed to ensure accurate staging.