Narrow Results

Human fibrocytes exhibit mixed phenotypic characteristics of haematopoietic stem cells, monocytes and fibroblasts, and originate from a precursor of the monocyte lineage. They constitutively produce chemokines and growth factors that are known to modulate inflammatory reactions or promote angiogenesis and the deposition of extracellular matrix molecules. Upon exposure to transforming growth factor-β₁ and endothelin-1, fibrocytes produce large quantities of extracellular matrix components and acquire a contractile phenotype. Such differentiation of fibrocytes into myofibroblast-like cells occurs at the tissue sites during repair processes and has been found to contribute to wound healing in vivo. Fibrocytes and fibrocyte-derived myofibroblasts are also involved in the pathogenesis of lung disorders characterised by chronic inflammation and extensive remodelling of the bronchial wall, like asthma, or progressive fibrosis with destruction of the pulmonary architecture, like idiopathic pulmonary fibrosis. They participate in tumour-induced stromal reactions and may either promote or inhibit the metastatic progression of cancers. Prevention of excessive extracellular matrix deposition and detrimental tissue remodelling in pulmonary diseases may be achieved by inhibiting the accumulation of fibrocytes in the lungs. Moreover, in vitro expanded fibrocytes may serve as vehicles for the delivery of gene constructs to improve ineffective lung repair or be used in anti-cancer cell therapy.

Demonstrating that a cell therapy can directly contribute to functional recovery of a diseased organ is made difficult by experimental methods that are liable to introduce false-positive data. In this chapter we analyze the methods used to prove that a transplanted cell has grafted into the target organ and highlight the potentials for producing misleading results. Furthermore, we discuss the advantages and pitfalls of supporting graft data by quantifying improvement of organ function. We conclude that a multi-tiered experimental approach is required to thoroughly dispel the notion that engraftment and functional improvement are artefactual. Because of the relative immaturity of the field of lung cell therapy, we draw many of our examples from tissues with related challenges, such as cardiomyocyte cell therapy.

Lung cancer is the most common cause of death from cancer. It is estimated that every 15 minutes in the UK, one person dies of lung cancer¹ and in both the UK and USA more people die of it than any other type of cancer,^2,3 it being responsible for about one quarter of all deaths from cancer. Its high mortality rate is also reflected on a global scale, with lung cancer accounting for more than 1 million deaths per year.⁴ Lung cancer is usually sub-divided into three types: small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and mesothelioma — a rare type of cancer that affects the pleura. Stem cells and cancer are inextricably linked; the perceived wisdom is that the process of carcinogenesis initially affects normal stem cells or their closely related progenitors, and then at some point, neoplastic stem cells are generated that propagate and ultimately maintain the process. Many, if not all cancers contain a population of self-renewing stem cells; the so-called cancer stem cells (CSCs) that are entirely responsible for sustaining the tumour as well as giving rise to proliferating but progressively differentiating cells that contribute to the cellular heterogeneity typical of many solid tumours. Thus tumours, like normal cell populations, may have a hierarchical structure. Adherents of the CSC hypothesis believe that the bulk of the tumour is therefore not the clinical problem, and so the identification of CSCs and the factors that regulate their behaviour are likely to have an enormous bearing on the way we treat neoplastic disease in the future. This chapter summarises 1) the histogenesis and molecular pathogenesis of lung tumours that probably take origin from normal pulmonary stem cells; 2) the evidence for the existence of CSCs in neoplastic lung tissue; and 3) illustrates some of the cellular pathways, often related to stem cell behaviour, that are frequently aberrant in lung cancer and may represent druggable targets.