Cancer cell biology and angiogenesis

The urokinase-type plasminogen activator (uPA) receptor (uPAR) has been implicated in signal transduction and biological processes including cancer metastasis, angiogenesis, cell migration, and wound healing. It is a specific cell surface receptor for its ligand uPA, which catalyzes the formation of plasmin from plasminogen, thereby activating the proteolytic cascade that contributes to the breakdown of extracellular matrix, a key step in cancer metastasis.

11p fptmusic 11-04-2013 46 3   Download

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.

6p konheokonmummim 03-12-2010 83 5   Download

Several general principles have arisen from these studies. Bevacizumab appears to potentiate the effects of many different types of active chemotherapeutic regimens used to treat a variety of different tumor types. No phase III trials have demonstrated single-agent activity for bevacizumab; colon and lung cancer trials have demonstrated a lack of activity when used alone. An exception may be renal cell cancer (RCC), a tumor that is specifically dependent upon VEGF as the result of deletion of the VHL tumor suppressor and activation of the HIF-1α transcription factor (see above).

5p konheokonmummim 03-12-2010 77 4   Download

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.

5p konheokonmummim 03-12-2010 81 6   Download

VEGF and its receptors are required for vasculogenesis (the de novo formation of blood vessels from differentiating endothelial cells, as occurs during embryonic development) and angiogenesis under normal (wound healing, corpus luteum formation) and pathologic processes (tumor angiogenesis, inflammatory conditions such as rheumatoid arthritis).

5p konheokonmummim 03-12-2010 76 6   Download

Normalization of tumor blood vessels due to inhibition of VEGF signaling. A. Blood vessels in normal tissues exhibit a regular hierarchical branching pattern that delivers blood to tissues in a spatially and temporally efficient manner to meet the metabolic needs of the tissue (top). At the microscopic level, tight junctions are maintained between endothelial cells (EC), which are adherent to a thick and evenly distributed basement membrane (BM). Pericytes form a surrounding layer that provides trophic signals to the EC and helps maintain proper vessel tone.

5p konheokonmummim 03-12-2010 70 4   Download

Tumor angiogenesis is a complex process involving many different cell types that must proliferate, migrate, invade, and differentiate in response to signals from the tumor microenvironment. Endothelial cells (ECs) sprout from host vessels in response to VEGF, bFGF, Ang2, and other proangiogenic stimuli. Sprouting is stimulated by VEGF/VEGFR2, Ang2/Tie-2, and integrin/extracellular matrix (ECM) interactions.

6p konheokonmummim 03-12-2010 81 7   Download

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.

5p konheokonmummim 03-12-2010 75 4   Download

New Concepts in the Development of Cancer Therapeutics Cancer Stem Cells It has long been recognized that only a small proportion of the cells within a tumor are capable of initiating colonies in vitro or of forming tumors at high efficiency when injected into immunocompromised NOD/SCID mice. Current work indicates that human acute and chronic myeloid leukemias (AML and CML) have a small population of cells (

5p konheokonmummim 03-12-2010 84 5   Download

Figure 80-6 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.

5p konheokonmummim 03-12-2010 89 5   Download

The release of apoptosis-inducing proteins from the mitochondria is regulated by pro- and antiapoptotic members of the Bcl-2 family. Antiapoptotic members (e.g., Bcl-2, Bcl-XL, and Mcl-1) associate with the mitochondrial outer membrane via their carboxy termini, exposing to the cytoplasm a hydrophobic binding pocket composed of Bcl-2 homology (BH) domains 1, 2, and 3 that is crucial for their activity.

5p konheokonmummim 03-12-2010 68 3   Download

Estrogen receptors (ERs) and androgen receptors, members of the steroid hormone family of nuclear receptors, are targets of inhibition by drugs used to treat breast and prostate cancers, respectively. Tamoxifen, a partial agonist and antagonist of ER function, can mediate tumor regression in metastatic breast cancer and can prevent disease recurrence in the adjuvant setting, saving thousands of lives each year. Tamoxifen binds to the ER and modulates its transcriptional activity, inhibiting activity in the breast but promoting activity in bone and uterine epithelium.

5p konheokonmummim 03-12-2010 78 5   Download

Acetylation of the amino terminus of the core histones H3 and H4 induces an open chromatin conformation that promotes transcription initiation. Histone acetylases are components of coactivator complexes recruited to promoter/enhancer regions by sequence-specific transcription factors during the activation of genes (Fig. 80-4). Histone deacetylases (HDACs; at least 17 are encoded in the human genome) are recruited to genes by transcriptional repressors and prevent the initiation of gene transcription.

5p konheokonmummim 03-12-2010 57 4   Download

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.

5p konheokonmummim 03-12-2010 83 5   Download

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.

5p konheokonmummim 03-12-2010 79 4   Download

Imatinib has also demonstrated targeted activity in other diseases, including gastrointestinal stromal tumors (GIST), rare mesenchymal tumors of the GI tract (stomach and small intestine). The pathogenic molecular event for most patients with this disease is mutation of the proto-oncogene c-Kit, leading to the constitutive activation of this receptor tyrosine kinase without the binding of its physiologic ligand, stem cell factor. About 10% of GISTs encode activating mutations of the PDGFRα instead of c-Kit.

5p konheokonmummim 03-12-2010 83 5   Download

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.

7p konheokonmummim 03-12-2010 109 5   Download

Telomerase DNA polymerase is unable to replicate the tips of chromosomes, resulting in the loss of DNA at the specialized ends of chromosomes (called telomeres) with each replication cycle. At birth, human telomeres are 15- to 20-kb pairs long and are composed of tandem repeats of a six-nucleotide sequence (TTAGGG) that associate with specialized telomere-binding proteins to form a T-loop structure that protects the ends of chromosomes from being mistakenly recognized as damaged.

5p konheokonmummim 03-12-2010 79 7   Download

Figure 80-1 Induction of p53 by the DNA damage and oncogene checkpoints. In response to noxious stimuli, p53 and mdm2 are phosphorylated by the ataxia telangiectasia mutated (ATM) and related ATR serine/threonine kinases, as well as the immediated downstream checkpoint kinases, Chk1 and Chk2. This causes dissociation of p53 from mdm2, leading to increased p53 protein levels and transcription of genes leading to cell cycle arrest (p21Cip1/Waf1) or apoptosis (e.g., the proapoptotic Bcl-2 family members Noxa and Puma).

5p konheokonmummim 03-12-2010 75 6   Download

Cancer Cell Biology The treatment of most human cancers with conventional cytoreductive agents has been unsuccessful due to the Gompertzian-like growth kinetics of solid tumors (i.e., tumor growth is exponential in small tumors, with increasing doubling times as tumors expand; since conventional chemotherapeutic agents target proliferating cells, noncycling cells in large tumors are relatively resistant). Genetic instability is inherent in most cancer cells and predisposes to the development of intrinsic and acquired drug resistance. Thus, although tumors arise from a single cell (i.e.

5p konheokonmummim 03-12-2010 93 5   Download