Corina Kim-Fuchs

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic microenvironment☆

Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.

Bioluminescent orthotopic model of pancreatic cancer progression.

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

The Silencing of N-myc Downstream-Regulated Gene-1 in an Orthotopic Pancreatic Cancer Model Leads to More Aggressive Tumor Growth and Metastases

Background: The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. Methods: Capan-1 cells were silenced for NDRG1 (Csil) or transfected with scrambled shRNA (Cscr) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. Results: The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). Conclusion: NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.

How to counter the problem of R1 resection in duodenopancreatectomy for pancreatic cancer

ObjectiveAlthough duodenopancreatectomy has been standardized for many years, the pathological examination of the specimen was re-described in the last years. In methodical pathological studies up to 85% had an R1 margin.1,2 These mainly involved the posterior und medial resection margin.3 As a consequence we need to optimize and standardize the pathological workup of the specimen and to extend the surgical resection, where possible without risk for the patient.Method and ResultIn an instructive video we show the technique of duodenopancreatectomy with emphasis on the dorsal and medial resection margin. Furthermore we show the standardized pathological workup of the specimen, involving the reporting of all the resection margins.ConclusionTo accurately determine R1 status at the posterior and medial resection margin, a close collaboration between pathologist and surgeon is crucial. Pathologists do a standardized workup of the resected specimen with staining of the surfaces and systematic analysis of all the resection margins. Surgeons need to extend the resection of the pancreatic head to the superior mesenteric artery by dorsal dissection.

Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention

The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.

Appendiceal Mucocele in an Elderly Patient: How Much Surgery?

Appendiceal mucoceles are rare cystic lesions with an incidence of 0.3–0.7% of all appendectomies. They are divided into four subgroups according to their histology. Even though the symptoms may vary – depending on the level of complication – from right lower quadrant pain, signs of intussusception, gastrointestinal bleeding to an acute abdomen with sepsis, most mucoceles are asymptomatic and found incidentally. We present the case of a 70-year-old patient with an incidentally found appendiceal mucocele. He was seen at the hospital for backache. The CT scan showed a vertebral fracture and a 7-cm appendiceal mass. A preoperative colonoscopy displayed several synchronous adenomas in the transverse and left colon with high-grade dysplasia. In order to lower the cancer risk of this patient, we performed a subtotal colectomy. The appendiceal mass showed no histopathological evidence of malignancy and no sign of perforation. The follow-up was therefore limited to 2 months. In this case, appendectomy would have been sufficient to treat the mucocele alone. The synchronous high-grade dysplastic adenomas were detected in the preoperative colonoscopy and determined the therapeutic approach. Generally, in the presence of positive lymph nodes, a right colectomy is the treatment of choice. In the histological presence of mucinous peritoneal carcinomatosis, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is indicated. In conclusion, mucoceles of the appendix are detected with high sensitivity by CT scan. If there is no evidence of synchronous tumor preoperatively and no peritoneal spillage, invasion or positive sentinel lymph nodes during surgery, a mucocele is adequately treated by appendectomy.

Pancreatic Neuroendocrine Tumors: How Much Surgery is Safe?

Background: Neuroendocrine tumors of the pancreas (pNET) are rare. Often the patients are asymptomatic for a long time and present late with metastasized disease. Although there are guidelines for the treatment of these tumors, there is no clear consensus whether the resection of liver metastases may be combined with the primary tumor. Method: We retrospectively analyzed the patients operated at our institution between 1/2003 and 12/2012. The patients were analyzed for demographic and clinical data, surgical treatment, tumor size and stage, histology, complications, survival and tumor recurrence over time. Results: We analyzed 53 patients, 23 females, 30 males. Patients with a one-step surgical approach to pancreas and liver had similar morbidity and mortality compared to patients with disease confined to the pancreas. The primary tumors were smaller in tumors confined to the pancreas. Angioinvasion as well as positive lymph nodes were strongly correlated with synchronous or metachronous liver metastases. Progression free survival was shorter in patients with primary metastasized disease. Conclusion: The treatment of pNET is challenging. The surgical approach should be tailored to the patient’s general condition. Patients benefit from extended and combined resections even in metastasized or locally advanced situations. Combined pancreatic and hepatic surgery may be performed safely.

37. Chronic stress promotes lymph node metastasis through beta-adrenergic regulation of lymphangiogenesis

Remodelling of tumor lymphatic vasculature facilitates tumor cell metastasis to lymph nodes. However, the physiological pathways that regulate lymphatic remodelling – or lymphangiogenesis – and lymphatic metastasis are yet to be defined. To investigate the impact of beta-adrenergic signaling on lymphangiogenesis and lymphatic metastasis, we explored the effect of restraint stress in an orthotopic xenograft model of triple negative breast cancer. Longitudinal bioluminescence imaging revealed that chronic stress reduced time to lymph node metastasis and increased tumor cell load in draining lymph nodes. Pharmacological activation of beta-adrenergic pathways similarly induced lymphatic remodelling and this effect was blocked with pharmacological beta-blockade. Chronic stress increased the expression of lymphangiogenic growth factor VEGFC and its receptor Vefgr3, and shRNA knock-down of VEGFC reversed the effect of stress on lymph vessel density within primary tumors. We recently found that inflammation increased dilation of lymphatic collector vessels to promote breast cancer metastasis. Consistent with those studies, we found that stress regulated VEGFC by modulating expression of pro-inflammatory COX-2. Treatment with COX-2 inhibitor celecoxib reversed stress-induced lymph vessel dilation and blocked stress-enhanced tumor lymphangiogenesis and lymph node metastasis. These data show that stress acts through a betaAR-inflammation-VEGFC axis to promote lymph node metastasis. Importantly, these studies identify critical opportunities for therapeutic intervention that may help protect women with breast cancer from the adverse effects of stress biology.

39. Chronic stress regulates pancreatic cancer progress: A critical role for beta-adrenergic signalling

Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS), however the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To investigate the effect of neural signaling on cancer progression we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of beta-adrenergic signaling induced similar effects to chronic stress, and pharmacological beta-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural-induced beta-adrenergic signaling regulates cancer progression within the pancreatic microenvironment and suggest beta-blockade as a novel strategy to complement existing therapies.