Gastrointestinal stromal tumor mesenchymal neoplasms: the offspring that choose the wrong path

Abstract

Gastrointestinal stromal tumors (GISTs) are relatively rare neoplasms of the gastrointestinal tract originating from the pluripotential mesenchymal stem cells, which differentiate into interstitial Cajal cells. They are usually located in the upper gastrointestinal track. These tumors are typically defined by the expression of c-KIT (CD117) and CD34 proteins in the tumor cells. A small percentage of these tumors is negative for c-KIT. The neoplasms are positive for platelet-derived growth factor α (PDGFα) mutations. In addition to PDGFRα mutations, wild-type c-KIT mutations can also be present. The therapeutic approach to locally developed gastrointestinal stromal tumors is surgical resection, either with open or laparoscopic surgery. In case of systemic disease, molecular pharmacologic agents such as imatinib and sunitinib are used for treatment. These agents block the signaling pathways of neoplastic-cell tyrosine kinases, interfering in their proliferation and causing apoptosis.

Keywords: GIST; PDGFRα; cancer pathways; interstitial cells of Cajal; mesenchymal stem cells.

Figure 1

Targeted therapy pathways. Notes: Protein kinase B (AKT) is a serine/threonine-specific protein kinase that affects glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. Together, RAS, c-RAF, MEK 1/2, RAS, and ERK 1/2 comprise the MAPK–ERK pathway, which is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell; it is also known as the “Ras–Raf–MEK–ERK pathway.” Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK–STAT pathway. Phosphoinositide 3-kinase (PI3K) is an important signaling pathway for growth control, metabolism, and translation initiation. The active sites of tyrosine kinases each have a binding site for adenosine triphosphate (ATP). Abbreviations: ERK, extracellular signal-regulated kinases; MAPK, mitogen-activated protein kinases; MTOR, mammalian target of rapamycin; STAT, signal transducer and activator of transcription.