Sustaining Proliferative Signaling

Growth factors are proteins, that although present at very low concentrations in tissues, exhibit high biological activity. They act locally where they bind to transmembrane receptors on cell membranes allowing them to participate in cell signalling. Being transmembrane, growth factor receptors are able to communicate signals from outside the cell to control essential functions within the cells. Cell signalling thereafter involves a complex intracellular cascade with tightly controlled mechanisms ensuring targeted downstream activation of genes that bring about the desired cellular growth, specialization, or survival.

Unfortunately, cancer cells have the ability to turn this orderly process awry. Unlike ‘normal’ cells, cancer cells do not require a ‘go ahead’ from growth factors to begin normal growth. Cancer cells are independent of growth factors thereby removing a critical checkpoint on the path towards cancer. There are three common strategies through which the cancer cells bypass this checkpoint.

• Cancer cells produce their own growth factors, that operate on a positive feedback loop.
• Cancer cells alter GF receptors so that they remain ‘switched on’
• Alterations occur further downstream of the signaling pathway. For example, one of the key downstream components of the growth factor signaling pathway is a protein known as Ras. Mutant Ras is permanently ‘switched on’. Mutant Ras is the most common gene in human cancer; 25% of all human tumors, and up to 90% of certain types of cancer such as pancreatic cancer have mutant Ras.

With these three strategies for achieving self-sufficiency in growth signals, the result is cells that are capable of growing uncontrollably, unstoppably and pathologically, i.e. Cancer Cells

Enhanced glycolysis is a well-recognised cancer phenotype that is associated with increased growth demands. In a study on pancreatic ductal adenocarcinoma it was shown that mutant Kras activity enhances glucose uptake and rewires glucose metabolism into the hexosamine biosynthesis and pentose phosphate pathways (Ying et al 2012). However, its metabolic impact on other cancer types and more importantly, that of KRAS mut copy gain was unclear. Using the Seahorse Kerr et all (Nature 2016) demonstrated that Kras G12D homozygosity caused increased glycolysis and increased glycolytic reserve while mitochondrial metabolism remained unchanged. 

Ras proteins belong to the super-family of small GTPase. The small GTPases are central mediators that act downstream of growth factor receptor signaling and are critical for cell proliferation, survival, and differentiation. When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in the above cell functions. Mutations in ras genes can lead to the production of permanently activated Ras proteins. Consequently, even with the lack of incoming signals, this can cause inadvertent and overactive signaling inside the cell. Since these signals lead to cell growth and division, overactive Ras signaling can ultimately lead to cancer. Kras, and Nras have been identified as the most common oncogenes in human cancer. More than 20-25% of human tumors have an activating point mutation in Ras, and up to 90% in certain types of cancer eg., pancreatic cancer. Kras mutations are particularly common in colon cancer, lung cancer, and pancreatic cancer. In the majority of cases, these mutations are missense mutations in codons 12, 13 and 61. 

The ATCC^® RAS genetic alteration cell panel (ATCC^® No. TCP-1031™) is a suitable tool to investigate Ras mutation. The RAS Genetic Alteration Tumor Cell Panel is composed of ten selected human tumor cell lines from various common cancer types that carry KRAS or NRAS hotspot mutations. The KRAS and NRAS status of each cell line has been sequenced and validated by ATCC. This panel is useful for growth factor receptor signaling pathway research, molecular diagnostic biomarker study, and anti-cancer drug discovery.

ATCC^® No. TCP-1031™ RAS Genetic Alteration Cell Panel

To find out more about ATCC Tumor Cell Panels visit the ATCC website 

The Tocris RAS Scientific Review provides a comprehensive overview of RAS protein function and RAS mutations in cancer.

Key signaling pathways are highlighted and therapeutic vulnerabilities are explored. This review also includes a detailed section on RAS drug discovery and targeting synthetic lethal interactors of mutant RAS.

A range of Tocris Compounds are available to support research in understanding RAS function in cytoplasmic signalling and the potential therapeutic role of anti-RAS therapy in Cancer.