The Problem with Cancer Models

Very few cancer drugs succeed in clinical trials, despite showing promise in the lab. Treatments that may work on animal models, cell lines, or even patient-derived xenografts often do not have the same efficacy in patients. The underlying reason is tumor environments within the human body are far more complex than in research models. For example, the tissue structure (histological complexity) and genetic heterogeneity of an animal model is different than that of humans. Even cell lines and patient-derived xenografts, which are human-derived, have their own pitfalls such as genetic mutations and animal-specific tumor evolution, respectively. Due to the inability to reproduce human tumor environments, many drugs fail clinical trials after lengthy and costly development.

The Hippo signal is very conservative in evolution. It regulates organ size and tissue stability by regulating cell proliferation, apoptosis, and stem cell renewal. The core process of Hippo signaling is a kinase tandem process, Mst1/2 and Sav1 form a complex, phosphorylate and activate Lats1/2; Lats1/2 kinase then phosphorylates and inhibits transcriptional coactivators Yap and Taz. Yap and Taz are the most important effectors downstream of the Hippo pathway. Upon dephosphorylation, Yap and Taz translocate to the nucleus and interact with TEAD1-4 or other transcription factors (such as CTGF) to induce gene expression, thereby initiating cell proliferation and inhibiting apoptosis.

Long-interspersed nuclear elements (LINEs) are genetic components found in higher eukaryotes. They are retrotranposons, meaning that they are transcribed into mRNA and then translated into proteins that act as a reverse transcriptase. The reverse transcriptase makes a copy of the LINE DNA which can then be integrated into the genome at a new site. The only active LINE in humans is LINE-1. It has been associated with oncogenesis and Haemophilia A, a diseased caused by insertional mutagenesis.

The extracellular signal-regulated kinases, or ERK1/2 (MAPK1/MAPK3, p44/42MAPK), are signaling molecules belonging to the mitogen-activated protein kinase family (MAPKs) that are commonly located in the cytoplasm of eukaryotic cells. In concert with various other molecules in the signaling cascade acting under different surface or intracellular receptors, ERK1/2 act as catalysts in the phosphorylation of serine/threonine and are negatively regulated by the bispecific (Thr/Tyr) MAPK phosphatase family (called DUSP or MKP) and specific inhibitors to MEK activity (such as U0126 and PD98059).

Astrocytes are specialized glial cells with distinct morphology that are found in the central nervous system, playing a role in brain and nerve cell development and the formation of synapses. Mature astrocytes respond to many stress signals and are responsible for many essential complex functions in the healthy brain, allowing the maintenance of proper homeostasis through ion flow, signaling, and the recycling of neurotransmitters. Astrocytes that are irregularly activated may result in various neurological disorders, including Alzheimer's disease and Huntington's disease. 

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is mainly found in astrocytes. It is also expressed in chondrocytes, fibroblasts, myoepithelial cells, lymphocytes, and hepatic stellate cells.

Although exosomes were discovered over five decades ago, interest among the scientific community didn’t pique until much later. Specifically, in the last ten years, the number of annual publications about exosomes have almost increased by tenfold (from 1,570 published papers in 2007 to 14,000 in 2017). But what exactly are exosomes and what justifies the frenzy?