https://www.cell.com/cell/pdfExtended/S0092-8674(09)01626-2

Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF

Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

/pdf/guidelines-for-the-welfare-and-use-of-animals-in-cancer-zlrmenfril.pdf

Guidelines for the welfare and use of animals in cancer research

Oncogenic Braf induces melanocyte senescence and melanoma in mice.

Lowering of tumor interstitial hypertension, which acts as a barrier for tumor transvascular transport, has been proposed as a general strategy to enhance tumor uptake and therapeutic effects of anticancer drugs. The tyrosine kinase platelet-derived growth factor (PDGF) beta-receptor is one mediator of tumor hypertension. The effects of PDGF antagonists on chemotherapy response were investigated in two tumor models that display PDGF receptor expression restricted to the tumor stroma, and in which PDGF antagonists relieve tumor hypertension. Inhibitory PDGF aptamers and the PDGF receptor tyrosine kinase inhibitor STI571 enhanced the antitumor effect of Taxol on s.c. KAT-4 tumors in SCID mice. Treatment with only PDGF antagonists had no effect on tumor growth. Taxol uptake in tumors was increased by treatment with PDGF antagonists. Cotreatment with PDGF antagonists and Taxol was not associated with antiangiogenic effects, and PDGF antagonists did not enhance the Taxol effect on in vitro growth of KAT-4 cells. STI571 also increased the antitumor effects of 5-fluorouracil on s.c. PROb tumors in syngeneic BDIX rats, without increasing the effect of 5-fluorouracil on cultured PROb cells. Expression of PDGF receptors in tumor stroma, as well as tumor hypertension, occurs in most common solid tumors. Therefore, our results have implications for treatment regimens for large patient groups and merit clinical testing. In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy.

https://cancerres.aacrjournals.org/content/canres/62/19/5476.full.pdf

Inhibition of PDGF Receptor Signaling in Tumor Stroma Enhances Antitumor Effect of Chemotherapy

We identified a previously undescribed gene associated with colon cancer by genome-wide expression analysis in primary and metastatic carcinomas: metastasis-associated in colon cancer-1, MACC1. MACC1 expression in tumor specimens is an independent prognostic indicator of metastasis formation and metastasis-free survival. We show that the gene encoding the hepatocyte growth factor (HGF) receptor, MET, is a transcriptional target of MACC1. MACC1 promotes proliferation, invasion and HGF-induced scattering of colon cancer cells in cell culture and tumor growth and metastasis in mouse models. These phenotypes are lost in cells expressing MACC1 mutants lacking the SH3 domain or the proline-rich motif. For clinical practice, MACC1 will be useful for the identification of poor prognosis subjects with colorectal cancer and is a promising new target for intervention in metastasis formation.

http://basicmed.med.ncku.edu.tw/admin/up_img/980410-1.pdf

MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis

UKCCCR guidelines for the welfare of animals in experimental neoplasia.

The Secretariat, UKCCCR, The Medical Research Council, 20 Park Crescent, London W1N 4AL, United Kingdom

https://link.springer.com/content/pdf/10.1007/BF00047059.pdf

C G Pierrepoint

Papers

UKCCCR guidelines for the welfare of animals in experimental neoplasia.

UKCCCR Guidelines for the welfare of animals in experimental neoplasia