RON () and HGFL () Co-Overexpression Supports Breast Tumorigenesis through Autocrine and Paracrine Cellular Crosstalk.

Background: Aberrant RON signaling is present in numerous cancers including breast cancer. Evidence suggests that the ligand, hepatocyte growth factor-like (HGFL), is also overexpressed in breast cancer. RON () and HGFL () genes are located on human chromosome 3 and mouse chromosome 9 respectively and are found near each other in both species.

Macrophage-mediated RON signaling supports breast cancer growth and progression through modulation of IL-35.

Tumor associated macrophages (TAMs) play a major role in regulating mammary tumor growth and in directing the responses of tumor infiltrating leukocytes in the microenvironment. However, macrophage-specific mechanisms regulating the interactions of macrophages with tumor cells and other leukocytes that support tumor progression have not been extensively studied. In this study, we show that the activation of the RON receptor tyrosine kinase signaling pathway specifically in macrophages supports breast cancer growth and metastasis.

Tumor cell intrinsic RON signaling suppresses innate immune responses in breast cancer through inhibition of IRAK4 signaling.

Increasing evidence suggests that cancer cells require both alterations in intrinsic cellular processes and the tumor microenvironment for tumor establishment, growth, and progression to metastatic disease. Despite this, knowledge of tumor-cell intrinsic molecular mechanisms controlling both tumor cell processes as well as the tumor microenvironment is limited. In this study, we provide evidence demonstrating the novel role of RON signaling in regulating breast cancer initiation, progression, and metastasis through modulation of tumor cell intrinsic processes and the tumor microenvironment.

HGFL-mediated RON signaling supports breast cancer stem cell phenotypes via activation of non-canonical β-catenin signaling.

Breast cancer stem cells (BCSCs), which drive tumor progression, recurrence, and metastasis, are considered a major challenge for breast cancer treatments, thus the discovery of novel pathways regulating BCSC maintenance remains essential to develop new strategies to effectively target this population and combat disease mortality. The HGFL-RON signaling is overexpressed in human breast cancers and is associated with increased breast cancer progression, metastasis, and poor prognosis. Here, we report that overexpression of RON/MST1R and HGFL/MST1 in cell lines and primary tumors increases BCSC self-renewal, numbers, and tumorigenic potential after syngeneic transplantation.

HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses.

The Ron receptor is overexpressed in human breast cancers and is associated with heightened metastasis and poor survival. Ron overexpression in the mammary epithelium of mice is sufficient to induce aggressive mammary tumors with a high degree of metastasis. Despite the well-documented role of Ron in breast cancer, few studies have examined the necessity of the endogenous Ron ligand, hepatocyte growth factor-like protein (HGFL) in mammary tumorigenesis.

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs.

Total parenteral nutrition (TPN) is associated with the development of parenteral nutrition-associated liver disease (PNALD) in infants. Fish oil-based lipid emulsions can reverse PNALD, yet it is unknown if they can prevent PNALD. We studied preterm pigs administered TPN for 14 days with either 100% soybean oil (IL), 100% fish oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fish oil (SL); a group was fed formula enterally (ENT).

Supplementing monosodium glutamate to partial enteral nutrition slows gastric emptying in preterm pigs(1-3).

Emerging evidence suggests that free glutamate may play a functional role in modulating gastroduodenal motor function. We hypothesized that supplementing monosodium glutamate (MSG) to partial enteral nutrition stimulates gastric emptying in preterm pigs. Ten-day-old preterm, parenterally fed pigs received partial enteral nutrition (25%) as milk-based formula supplemented with MSG at 0, 1.

GLP-2 delays but does not prevent the onset of necrotizing enterocolitis in preterm pigs.

Objectives: Necrotizing enterocolitis (NEC) is complex disease thought to occur as a result of an immaturity of the gastrointestinal tract of preterm infants. Intestinal dysfunction induced by total parental nutrition (TPN) may increase the risk for NEC upon introduction of enteral feeding. We hypothesized that the intestinal trophic and anti-inflammatory actions previously ascribed to the gut hormone, glucagon-like peptide-2 (GLP-2), would reduce the incidence of NEC when given in combination with TPN in preterm piglets.

Ron receptor tyrosine kinase signaling as a therapeutic target.

Introduction: Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis.

Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice.

Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesized that orally administered MTA would be bioavailable and reduce morbidity associated with experimental colitis.

Continuous parenteral and enteral nutrition induces metabolic dysfunction in neonatal pigs.

Background: We previously showed that parenteral nutrition (PN) compared with formula feeding results in hepatic insulin resistance and steatosis in neonatal pigs. The current aim was to test whether the route of feeding (intravenous [IV] vs enteral) rather than other feeding modalities (diet, pattern) had contributed to the outcome.

Methods: Neonatal pigs were fed enterally or parenterally for 14 days with 1 of 4 feeding modalities as follows: (1) enteral polymeric formula intermittently (FORM), (2) enteral elemental diet (ED) intermittently (IEN), (3) enteral ED continuously (CEN), and (4) parenteral ED continuously (PN).

B-vitamin deficiency is protective against DSS-induced colitis in mice.

Vitamin deficiencies are common in patients with inflammatory bowel disease (IBD). Homocysteine (Hcys) is a thrombogenic amino acid produced from methionine (Met), and its increase in patients with IBD indicates a disruption of Met metabolism; however, the role of Hcys and Met metabolism in IBD is not well understood. We hypothesized that disrupted Met metabolism from a B-vitamin-deficient diet would exacerbate experimental colitis.

Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis.

Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis. Peroxisome proliferator-activated receptor (PPAR) gamma suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPARgamma abundance.