Carcinoma cells can transition from an epithelial to mesenchymal differentiation state through a process known as epithelial-mesenchymal transition (EMT). The process of EMT is characterized by alterations in the pattern of gene expression and is associated with a loss of cell polarity, an increase in invasiveness and an increase in cells expressing cancer stem cell (CSC) markers. The reverse process of mesenchymal to epithelial transition (MET) can also occur, though the transitions characterizing EMT and MET can be incomplete. A growing number of transcription factors have been identified that influence the EMT/MET processes. Interestingly, SUMOylation regulates the functional activity of many of the transcription factors governing transitions between epithelial and mesenchymal states. In some cases the transcription factor is SUMO conjugated directly, thus altering its transcriptional activity or cell trafficking. In other cases, SUMOylation alters transcriptional mechanisms through secondary effects. The current review explores the role of SUMOylation in controlling transcriptional mechanisms that regulate EMT/MET in cancer. Developing new drugs that specifically target SUMOylation offers a novel therapeutic approach to block tumor growth and metastasis.

SummaryMany solid cancers have an expanded CD44+/hi/CD24−/low cancer stem cell (CSC) population, which are relatively chemoresistant and drive recurrence and metastasis. Achieving a more durable response requires the development of therapies that specifically target CSCs. Recent evidence indicated that inhibiting the SUMO pathway repressed tumor growth and invasiveness, although the mechanism has yet to be clarified. Here, we demonstrate that inhibition of the SUMO pathway repressed MMP14 and CD44 with a concomitant reduction in cell invasiveness and functional loss of CSCs in basal breast cancer. Similar effects were demonstrated with a panel of E1 and E3 SUMO inhibitors. Identical results were obtained in a colorectal cancer cell line and primary colon cancer cells. In both breast and colon cancer, SUMO-unconjugated TFAP2A mediated the effects of SUMO inhibition. These data support the development of SUMO inhibitors as an approach to specifically target the CSC population in breast and colorectal cancer.

Purpose Recent findings suggest that combination treatment with anti-estrogen and anti-RET may offer a novel treatment strategy in a subset of breast cancer patients. We investigated the role of RET in potentiating the effects of anti-estrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect ERK1/2 activation in primary breast cancer. Experimental Design Growth response, ERK1/2 activation, Ki-67 and TUNEL were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. Results Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (p=0.01) and hormone insensitive (p<0.001) ERα-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (p<0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared to single agent (p=0.003), with tamoxifen reducing proliferative index and vandetanib inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (p<0.001) in RET-positive tumors vs. 14% (p=ns) in RET-negative tumors. Conclusions Vandetanib potentiated the anti-growth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of anti-estrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer.

Renal neuroendocrine neoplasms are rare, with descriptions of cases limited to individual reports and small series. The natural history of this group of neuroendocrine neoplasms is poorly understood. In this study, we queried the Surveillance, Epidemiology and End Results (SEER) database over a four-decade period where we identified 166 cases of primary renal neuroendocrine neoplasms. We observed a 5-year overall survival of 50%. On multivariate analysis, survival was influenced by stage, histology, and if surgery was performed. We observed that patients managed by operative management had a greater frequency of localized or regional stage disease as well as a greater frequency of neuroendocrine tumor, grade 1 histology; whereas those managed non-operatively tended to have distant disease and histologies of neuroendocrine carcinoma, NOS and small cell neuroendocrine carcinoma. This is the largest description of patients with renal neuroendocrine neoplasms. Increased survival was observed in patients with earlier stage and favorable histologies.

Positive peritoneal cytology (Cyt+) is an important staging tool for patients with locally advanced gastric cancer. The objective of this review is to evaluate the current literature regarding cytology evaluation in patients with gastric cancer and to provide recommendations on the inclusion of this powerful prognosticator in patients with this disease. A literature search was performed for recent and pertinent studies evaluating peritoneal cytology in patients with gastric adenocarcinoma. Peritoneal cytology as the only evidence for M1 disease is present in up to 10% of patients with locally advanced gastric cancer; survival in the setting of Cyt+ is dismal when gastrectomy is the first line of therapy. Improved survival is associated with response to chemotherapy indicated by conversion to negative cytology, good performance status, and antral tumors. Highly select patients with Cyt+ treated with gastrectomy show improved survival in only some of the available studies. There are high quality studies that support the routine practice of peritoneal cytology evaluation in patients with locally advanced gastric cancer. The role of gastrectomy remains unclear in patients with Cyt+ and clinical trials are needed to define the best treatment option for this select group of patients.