The ultraprecise wiring of neurons banks on the instructions provided by guidance cue proteins that steer them to their appropriate target tissue during neuronal development. Semaphorins are one such family of proteins. Semaphorins are known to play major physiological roles during the development of various organs including nervous system, cardiovascular, and immune systems. Their role in different pathologies including cancer remains an intense area of investigation. This review focuses on a novel member of this family of proteins, semaphorin 5A, which is much less explored in comparison to its other affiliates. Recent reports suggest that semaphorins play important roles in the pathology of cancer by affecting angiogenesis, tumor growth and metastasis. We will firstly give a general overview of the semaphorin family and its receptors. Next, we discuss their roles in cellular movements and how that makes them a connecting link between nervous system and cancer. Finally, we focus our discussion on semaphorin 5A to summarize the prevailing knowledge for this molecule in developmental biology and carcinogenesis.
Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor survival. Somatic KRAS mutations are present in almost 95% of PDAC patients and are known to a play pivotal role in PDAC genesis and progression. The G12D substitution is the predominant form detected in PDAC. By constitutively activating diverse downstream signaling pathways (like ERK/MEK) KRAS mutations are known to drive autocrine growth transformation in cancer cells. However, the lack of therapeutics for direct targeting of mutant KRAS necessitate a proper understanding of its downstream mechanisms, which may aid in the development of specific therapeutics. CXCR2 is a receptor for the ELR-positive CXC subfamily of chemokines, which are established regulators of leukocyte chemotaxis during inflammation. Aberrant expression of CXCR2 and its ligands has been reported in various cancers including PDAC. Both autocrine and paracrine events mediated by CXCR2 signaling lead to the manifestation of tumor growth, metastasis and angiogenesis. RAS is a known regulator of cytokine production including CXC chemokines. Whilst much of the work done formerly has indicated a paracrine role for KRAS-induced production of CXC chemokines in the biology of PDAC the precise autocrine effects of KRAS induced CXCR2 signaling remain uncertain. We examined the tumors derived from PDX-cre-LSL-kras(G12D) mice and observed a specific expression of Cxcr2 in the cytokeratin positive duct cells. Based on this preliminary observation the objective of our current study is to evaluate the autocrine role of CXCR2 signaling in the KRAS(G12D) -induced PDAC development. Two human cell line models having exogenously expressed KRAS(G12D): hTERT-HPNE-/KRAS(G12D) and hTERT-HPNE-E6-E7-st/KRAS(G12D) were used for our in vitro studies. CXCR2 inhibition achieved using antagonists (SCH-527123 and SCH-479833) significantly (P ≤ 0.05) suppressed the in vitro proliferation, anchorage independent growth and migration potential of KRAS(G12D) bearing cells in a dose dependent manner. We generated stable clones of hTERT-HPNE-E6-E7-st/KRAS(G12D) cells having knock-down for CXCR2. Complementing our observations from CXCR2 inhibition the hTERT-HPNE-E6-E7-st/KRAS(G12D)-shCXCR2 cells demonstrated a significant (P ≤ 0.05) decrease in in vitro cell growth, colony formation and migration compared to the control cells. Additionally, both hTERT-HPNE-E6-E7-st/KRAS(G12D)-shCXCR2 cells and hTERT-HPNE-E6-E7-st/KRAS(G12D) cells treated with SCH-527123 demonstrated inhibited phosphorylation of Erk downstream of KRAS. We next extended our investigation in vivo. The hTERT-HPNE-E6-E7-st/KRAS(G12D)-shCXCR2 cells showed reduced tumor growth compared to the control cells in subcutaneous implants. To conclude, our data provides evidence for the role of the CXCR2 signaling axis in regulation of KRAS(G12D) induced autocrine cellular transformation in PDAC. Citation Format: Abhilasha Purohit, Michelle Varney, Satya Rachagani, Pavan Myneni, Michel Ouellette, Surinder K. Batra, Rakesh K. Singh. Targeting CXCR2 signaling inhibits KRAS(G12D) induced autocrine growth transformation by suppressing ERK activation in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3178. doi:10.1158/1538-7445.AM2015-3178
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