Stem Cells Between Regeneration and Tumorigenesis

The discovery of hematopoietic stem cells (HSCs) ushered in a new era in stem cell and life science research. Much of the technology and knowledge that has been gained through HSC studies is now applied in many fields of biology and has fundamentally changed our understanding of stem cells. For example, cell identification and purification using cell surface markers, which were developed and fine-tuned in HSC studies, are now routinely used to investigate the developmental stages of different cell populations not only in hematopoiesis but also in the development of other organs and in tumor biology. The therapeutic benefits of HSCs have long been recognized as bone marrow transplants have saved many lives, and with an increasing understanding of HSC biology and its translation to the clinic, studies of HSCs will continue to benefit the health of humans and our curiosity of life in general. In this chapter, we will briefly describe the discovery, regulation, and therapeutic application of HSCs. We apologize that many studies are not included here due to the nature of this review.

This chapter focuses on the epithelial stem cells in oral mucosa. It starts with the characterization of the normal epithelial stem cells (location, methods of identification, stemness markers). Next, it discusses the concept of cancer stem cells: origin, cancer stem cell markers, cancer stem cells niche and interference with treatment. Finally, the chapter discusses the role of oral stem cells in oral mucosa wound repair.

This chapter will highlight the main characteristics of processes like regeneration and tumorigenesis in skin. The chapter describes the skin regeneration pathways and it elaborates on interesting link regarding regeneration triggering tumorigenesis in cutaneous tissue. Stem cells that are the key player in non-melanoma and melanoma skin cancers will be described in separate sections.

The neural stem cell niche in the adult brain is a complex environment formed by several types of cells, a particular type of extracellular matrix and specific molecular cues. Ageing is characterized by reduced neurogenesis, due to altered neurotrophin signaling, activation of senescence programmes within the niche, imbalanced growth factor signalling. A recent concept is that blood-born ageing factors signal or cross the blood brain barrier to negatively influence the neurogenesis. Neurodegenerative diseases are an appealing target for regenerative medicine and stem cell transplant was held for quite some time in high consideration and brought about high hopes for the replacement of lost cells and tissue function restoration. One of the major drawbacks is that most transplanted cells differentiate on glial line; therefore, new strategies were implemented. From transplantation of committed neuronal progenitors, to neurosphere transplant or autologous mesenchymal stem cells, these strategies are presented and some of the drawbacks highlighted in the present chapter.

The presence of cancer stem cells in brain tumors has been suggested in the recent years, extrapolating from other types of malignancies. The actual debate centers on the possibility that this small group of cells or a single cell can initiate and maintain such an aggressive malignancy status. Cancer stem cells are a major theme for aggressive brain tumors, their extensive study offering potential biomarkers for identification of therapy targets based on abnormal and connected signaling pathways. This chapter presents the phenomenology of cancer stem cells in their microenvironment, in its astonishing complexity. Identification markers, pathologic signaling profiles and cross-talk, microenvironment interactions and novel therapies targeting cancer stem cells are discussed. Continuous studies are researching genetic and epigenetic modifications associated with malignant evolution in glioma cancer stem cells. From the complex entangled signaling pathways presented, one must extract only the important molecules involved in oncogenesis onset and propagation, putting aside the coincidentally modified molecules that can be misleading. After removing the “smoke screen” of oncogenic irrelevant, but modified molecules, there remain the true therapy targets, to address by specific therapies in a combined manner to overcome the adapting processes governed by signaling pathway cross-talk.

Stem cells were first identified in adult organs with high regenerative capacity including skin, liver, intestine and bone marrow. The pituitary gland is an organ with low cell turnover, and while differentiated cells can re-enter the cell cycle, most hormone producing cells are not dividing. The adult pituitary gland has some capacity to regenerate after tissue injury. Recent studies have reported potential populations of stem cells in the pituitary. Stem cells population belongs to the chromophobe/folliculo-stellate population of adenohypophysis. Studies to date suggest that at least a part of the endocrine cells originates from marginal layer adjacent to Rathke’s cleft. Different groups, using diverse approaches, have demonstrated the presence in the pituitary of cells with progenitor or stem cell capacities and have characterized the pituitary stem cells, progenitors, and transit amplifying cells. A large variety of markers used to identify pituitary progenitors and stem cells make the integrated view difficult over the results obtained. Until now the nature of pituitary stem cells remains a matter of debate, and additional studies are needed to define the progenitors and stem cells in adenohypophysis.

The objective of the present chapter is to discuss the identification of cancer stem cells (CSC) in pancreatic ductal adenocarcinomas (PDAs) and hepatocellular carcinoma (HCC) and to briefly overview the current therapies targeting this cell population. The reason to restrict the discussion to these particular cancer types is that both are described by a poor prognosis and resistance to conventional therapies. Therefore, CSC may be an important hint in improving the therapeutic approach in both instances. Due to the capacity of CSC to escape chemo and radiotherapy, novel means of approaching these cells are necessary in order to improve outcome therapeutically.

This chapter will focus on the main immunological issues in stem cell approaches. The scientific world faces an important immunological dilemma when investigating stem cells immunogenicity. One is the need to have low stem cell’s immunogenicity, property that provides modest inflammatory reaction microenvironment and hence lack of rejection of the transplanted stem cells. On the other side any neoplastic transformation can increase the natural immune evasive properties of stem cells linking immune escape and tumorigenicity. In this light oncogenes expression can directly orchestrate inflammation and immune escape to drive the multistep process of cancer progression, independent of any immuno-editing in the tumor microenvironment. The chapter starts with characterizing the immunogenicity of stem cells, where major histocompatibility expression is the immune mold that can drive toward generation or tumorigenesis. The chapter continues with the processes that are involved in stem cells modulating the immune system elements whether in Regeneration or Tumorigenesis. The chapter ends with the main immune hurdles in the most recent clinical trials using stem cells.

Recent studies on stem cells and protein interactions using proteomics approaches have yielded novel perception on processes regulating development and stem cell biology. The development of stem cell approaches has evolved in the postgenomic era and the implementation of proteomic applications represents a great challenge.

Understanding the mechanism that controls stem cell pluripotency, self-renewal and differentiation will also improve the ability to develop stem cell-based therapies.

Current proteomics studies of stem cell signaling pathway can lead to the discovery of molecular mechanisms that govern cell-cell interaction and/or with stem cell niche.

Stem cells represent an important potential therapeutical approach, both in regenerative medicine and tumor pathology, allowing the understanding of the mechanisms that underlie the biology of these cells.

This chapter gives an overview of the new micro- and nano-technologies designed to monitor SC differentiation in the context of their potential applications in disease modeling, tissue engineering, regenerative medicine, as well as drug screening and toxicology. Representative examples of such applications are presented and the crucial importance of the differentiation processes for the safety of SC therapies is discussed. The roles of the main factors that influence SC differentiation are briefly summarized and the vital need to control and monitor the differentiation process using non-invasive methods is emphasized. The basic principles of new micro- and nanotechnologies for monitoring SC differentiation are presented, with special focus on the use of acoustic vibrational fields to characterize SC. Literature studies on SC differentiation, involving methods based on Impedance Sensing (IS), Surface Enhanced Raman Spectroscopy (SERS), Fourier Transformed Infrared (FTIR) spectroscopy, Microelectrode Array (MEA) sensors, Light-addressable Potentiometric Sensors (LAPS), Field-effect Transistors (FET), Surface Plasmon Resonance (SPR) and Quartz Crystal Microbalance (QCM), are briefly described.