Over the last three decades, knowledge on the molecular biology of human cancers has vastly expanded. A host of genes and proteins involved in cancer development and progression have been defined and many mechanisms at the molecular, cellular and even tissue level have been, at least partly, elucidated. Insights have also been gained into the molecular mechanisms underlying carcinogenesis by chemical, physical, and biological agents and into inherited susceptibility to cancer. Accordingly, Part I of the book presents many of the molecules and mechanisms generally important in human cancers.
This book describes a course of cancer growth starting from normal cells to cancerous form and the genomic instability, the cancer treatment as well as its prevention in form of the invention of a vaccine. Some diseases are also discussed in detail, such as breast cancer, leucaemia, cervical cancer, and glioma. Understanding cancer through its molecular mechanism is needed to reduce the cancer incidence.
Prostate cancer is the most common male cancer diagnosed in Western populations.
Autopsy studies have shown that with increasing age, the majority of
men will develop microscopic foci of cancer (often termed “latent” prostate
cancer) and that this is true in populations that are at both high and low risk for
the invasive form of the disease (1). However, only a small percentage of men
will develop invasive prostate cancer. The prevalence of prostate cancer is,
thus, very common; but to most men, prostate cancer will be only incidental to
their health and death....
Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer treatment. Acquired drug resistance of tumor cells due to their high intrinsic mutation rate is a major cause of treatment failure in human cancers. ECs comprising the tumor vasculature are genetically stable and do not share genetic changes with tumor cells; the EC apoptosis pathways are therefore intact.
Targeting BCR-ABL with Imatinib: Proof of Principle The protein product of the Philadelphia chromosome occurs in all patients with chronic myeloid leukemia (CML) and in ~30% of patients with adult acute lymphoid leukemia (ALL) and encodes the fusion protein Bcr-Abl. Although the c-Abl protooncogene is a nuclear protein whose kinase activity is tightly regulated as a part of the DNA damage response pathway (and actually induces growth arrest), the Bcr-Abl fusion protein is largely cytoplasmic with a constitutively activated tyrosine kinase domain.
PI3K is a heterodimeric lipid kinase that catalyses the conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate (PIP3), which acts as a plasma membrane docking site for proteins that contain a pleckstrin homology (PH) domain. These include the serine/threonine kinases Akt and PDK1 that are key downstream effectors of PI3K action (Fig. 80-2). The PI3K pathway is activated in 30–40% of human cancers and is thought to play a critical role in tumor cell survival, proliferation, growth, and glucose utilization.
Oncogene signaling pathways are activated during tumor progression and promote metastatic potential.
This figure shows a cancer cell that has undergone epithelial to mesenchymal transition (EMT) under the influence of several environmental signals. Critical components include activated transforming growth factor beta (TGF-β) and the hepatocyte growth factor (HGF)/c-Met pathways, as well as changes in the expression of adhesion molecules that mediate cell-cell and cellextracellular matrix interactions.
The bevacizumab experience suggests that inhibition of the VEGF pathway will be most efficacious when combined with agents that directly target tumor cells. This also appears to be the case in the development of small-molecule inhibitors (SMI) that target VEGF receptor tyrosine kinase activity but are also inhibitory to other kinases that are expressed by tumor cells and important for their proliferation and survival.
Signaling Pathways Downstream of Rtks: Ras and PI3K Several oncogene and tumor-suppressor gene products are components of signal transduction pathways that emanate from RTK activation (Fig. 80-2). The most extensively studied are the Ras/mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol-3-kinase (PI3K) pathway, both of which regulate multiple processes in cancer cells, including cell cycle progression, resistance to apoptotic signals, angiogenesis, and cell motility.
Oncogene Addiction and Synthetic Lethality The concepts of oncogene addiction and synthetic lethality have spurred new drug development targeting oncogene and tumor-suppressor pathways. As discussed earlier in this chapter and outlined in Fig. 80-3, cancer cells become physiologically dependent upon signaling pathways containing activated oncogenes; this can effect proliferation (i.e.
Several bacteria, including Azotobacter vinelandii, possess an alternative
pathway ofl-rhamnose metabolism, which is different from the known
bacterial pathway. In a previous article, a gene cluster related to this path-way was identified, consisting of the genes encoding the four metabolic
enzymes l-rhamnose-1-dehydrogenase (LRA1), l-rhamnono-c-lactonase
Across evolution, the signal recognition particle pathway
targets extra-cytoplasmic proteins to membranous trans-location sites. Whereas the pathway has been extensively
studied in Eukarya and Bacteria, little is known of this sys-tem in Archaea. In the following, membrane association of
FtsY, the prokaryal signal recognition particle receptor, and
SRP54, a central component of the signal recognition par-ticle, was addressed in the halophilic archaea Haloferax
In recent studies on heme-copper oxidases a particular glutamate residue in
subunit II has been suggested to constitute the entry point of the so-called
K pathway. In contrast, mutations of this residue (E78
) in the Paracoccus
denitrificanscytochromecoxidase do not affect its catalytic activity at all
Q) or reduce it to about 50% (E78
A); in the latter case, the mutation
causes no drastic decrease in hemea3
reduction kinetics under anaerobic con-ditions, when compared to typical K pathway mutants....
The Wnt pathway controls biological processes via the regulation of target
gene expression. The expression of direct Wnt target genes, e.g.cyclin D1
and MYC, is activated by the transcription factor TCF, which binds to
specific sequence motifs in the promoter. Indirect target genes are regulated
via transcription regulators, which are targets of the Wnt pathway.
Different pathways of bilayer disruption by the structurally
related antimicrobial peptides cecropin B, B1 and B3,
revealed by surface plasma resonance analysis of immobi-lized liposomes, differential scanning calorimetryof peptide–
large unilamellar vesicle interactions, and light microscopic
analysis of peptide-treated giant unilamellar vesicles, have
been identified inthis study.
Activation of hepatic stellate cells (HSCs), which is regulated by multiple
signal transduction pathways, is the key event in liver fibrosis. Moreover,
members of these pathways are important targets for microRNAs (miR-NAs). To better understand the critical pathways of HSC activation, we
performed comprehensive comparative bioinformatics analysis of micro-arrays of quiescent and activated HSCs.
Mannose for mammalian glycan biosynthesis can be imported directly from
the medium, derived from glucose or salvaged from endogenous or external
glycans. All pathways must generate mannose 6-phosphate, the activated
form of mannose.
The aromatic hydrocarbon receptor (AhR)-dependent pathway involved
in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity
has been studied extensively, but the AhR-independent molecular mechan-ism has not. In previous studies we found that the AhR is not expressed
in L-MAT, a human lymphoblastic T-cell line. In this report, we provide
the following evidence that the protein kinase C (PKC)hactivity is func-tionally involved in the AhR-independent signal transduction mechanism
that participates in the TCDD-induced L-MAT cell apoptosis....
Oxysterols, and particularly 7-ketocholesterol, appear to be strongly
involved in the physiopathology of atherosclerosis. These molecules are
suspected to be cytotoxic to the cells of the vascular wall and mono-cytes⁄macrophages, particularly by inducing apoptosis. Previous studies
have demonstrated that 7-ketocholesterol-induced apoptosis is triggered by
a sustained increase of cytosolic-free Ca
, which elicits the mitochondrial
pathway of apoptosis by activation of the calcium-dependent phosphatase
calcineurin, leading to dephosphorylation of the ‘BH3 only’ protein BAD....
The currently applied reaction structure in stoichiometric flux balance mod-els for the nonoxidative branch of the pentose phosphate pathway is not
in accordance with the established ping-pong kinetic mechanism of the
enzymes transketolase (EC 18.104.22.168) and transaldolase (EC 22.214.171.124). Based
upon the ping-pong mechanism, the traditional reactions of the nonoxida-tive branch of the pentose phosphate pathway are replaced by metabolite
specific, reversible, glycolaldehyde moiety (C2
) and dihydroxyacetone moi-ety (C3) fragments producing and consuming half-reactions. ...