Hedgehog signalling as a target in cancer stem cells

[Abstract] Hedgehog (Hh) is one of the most important signalling pathways. Together with the Wnt, TGF-β/BMP and Notch pathways, it is involved in both embryonic development and adult tissue homeostasis. This is because Hh plays a central role in the proliferative control and differentiation of both embryonic stem cells and adult stem cells. In this way, an alteration in the Hh pathway, either by misexpression of components of that pathway or by changes in the expression of other cellular components that interfere with the Hh signalling system, may trigger the development of several types of cancer. This occurs because normal stem cells or their intermediaries toward differentiated mature cells are not part of the normal proliferative/differentiation balance and begin to expand without control, triggering the generation of the so-called cancer stem cells. In this review, we will focus on the molecular aspects and the role of Hh signalling in normal tissues and in tumour development

Crossing paths in Human Renal Cell Carcinoma (hRCC)

[Abstract] Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways

Multiple biomarker tissue arrays: a computational approach to identifying protein-protein interactions in the EGFR/ERK signalling pathway

[Abstract] Background. Many studies have demonstrated genetic and environmental factors that lead to renal cell carcinoma (RCC) and that occur during a protracted period of tumourigenesis. It appears suitable to identify and characterise potential molecular markers that appear during tumourigenesis and that might provide rapid and effective possibilities for the early detection of RCC. EGFR activation induces cell cycle progression, inhibition of apoptosis and angiogenesis, promotion of invasion/metastasis, and other tumour promoting activities. Over-expression of EGFR is thought to play an important role in tumour initiation and progression of RCC because up-regulation of EGFR has been associated with high grade cancers and a worse prognosis. Methods. Characterisation of the protein profile interacting with EGFR was performed using the following: an immunohistochemical (IHC) study of EGFR, a comprehensive computational study of EGFR protein-protein interactions, an analysis correlating the expression levels of EGFR with other significant markers in the tumourigenicity of RCC, and finally, an analysis of the utility of EGFR for prognosis in a cohort of patients with renal cell carcinoma. Results. The cases that showed a higher level of this protein fell within the clear cell histological subtype (p = 0.001). The EGFR significance statistic was found with respect to a worse prognosis. In vivo significant correlations were found with PDGFR-β, Flk-1, Hif1-α, proteins related to differentiation (such as DLL3 and DLL4 ligands), and certain metabolic proteins such as Glut5. In silico significant associations gave us a panel of 32 EGFR-interacting proteins (EIP) using the APID and STRING databases. Conclusions. This work summarises the multifaceted role of EGFR in the pathology of RCC, and it identifies EIPs that could help to provide mechanistic explanations for the different behaviours observed in tumours

Notch signalling in cancer stem cells

[Abstract] A new theory about the development of solid tumours is emerging from the idea that solid tumours, like normal adult tissues, contain stem cells (called cancer stem cells) and arise from them. Genetic mutations encoding for proteins involved in critical signalling pathways for stem cells such as BMP, Notch, Hedgehog and Wnt would allow stem cells to undergo uncontrolled proliferation and form tumours. Taking into account that cancer stem cells (CSCs) would represent the real driving force behind tumour growth and that they may be drug resistant, new agents that target the above signalling pathways could be more effective than current anti-solid tumour therapies. In the present paper we will review the molecular basis of the Notch signalling pathway. Additionally, we will pay attention to their role in adult stem cell self-renewal, and cell fate specification and differentiation, and we will also review evidence that supports their implication in cancer

Biology of BMP signalling and cancer

[Abstract] In recent years, it has been proposed that tumours are not homogeneous but composed of several cellular types like normal tissues. A cellular subtype, which is though to be the origin of tumours as well as their malignant properties (i.e., capacity for regrowth and metastasis), are the cancer stem cells (CSCs). CSCs, like normal stem cells, have a nearly unlimited capacity to self-renew and to proliferate so that are responsible, besides their same auto-perpetuation giving rise to the features previously depicted, also for the generation of the bulk of more differentiated cells in tumour. The altered behaviour of CSCs may be caused by the malfunction of a number of signalling pathways involved in normal embryonic development and in tissue homeostasis in adulthood. Among these signalling pathways are Wnt, Hedgehog, Notch and BMP pathways. In this review, we will focus on the study of molecular aspects of BMP signalling as well as its involvement in cancer