BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E.S. Severin - 2004

CHAPTER 16. ONCOGENESIS

II. Characteristics of Tumor Cells

Differentiated Cells respect tissue boundaries and do not invade adjacent territories, obeying the rule of contact inhibition. During transformation, this property is lost.

Tumor cells typically have a rounded or stellate shape and are larger than normal cells. Their nuclear-cytoplasmic ratio is altered, and they exhibit either polyploidy (a condition in which The Nucleus contains 3 or more haploid sets of Chromosomes) or aneuploidy, where the chromosome number changes and becomes non-multiple of the haploid set. Due to a reduced capacity for adhesion, they can grow without attaching to a surface and form multilayers.

A. Metabolic Features

The METABOLISM of tumor cells exhibits A number of characteristic features that grant them significant advantages over normal cells. Specifically, in Cancer cells:

✵ The activity of Ribonucleotide reductase increases, while the Catabolism of Pyrimidines and Purines decreases, leading to enhanced DNA and RNA Synthesis;

✵ The rate of Glycolysis (both aerobic and anaerobic) increases, along with elevated lactate production. The heightened lactate secretion characteristic of many tumors is known as the "Warburg effect." Predominant anaerobic glycolysis appears to be not an intrinsic property of tumor cells, but rather a consequence of rapid growth under conditions of a poorly developed Blood vessel network; studies have established that the less differentiated the tumor and the higher its growth rate, the more intensive its anaerobic glycolysis and the weaker its Oxidative Phosphorylation;

✵ the isoenzyme spectrum of various Proteins and Enzymes shows an increased content of fetal forms. In Carbohydrate Metabolism, for example, these include Phosphofructokinase (which is not inhibited by ATP and citrate), a hexokinase isoenzyme characterized by an extremely high affinity for glucose, and a highly active Lactate dehydrogenase.

Such alterations provide the cancer Cell with an extremely high affinity for glucose and The ability to assimilate it even at very low blood concentrations. Similar shifts in the isoenzyme spectrum are observed in other metabolic pathways as well, enabling tumor cells to successfully compete with surrounding Tissues for vital metabolites.

B. Appearance of Embryonic Proteins and Enzymes

These cells synthesize, and sometimes secrete into the bloodstream, embryonic proteins and Antigens, such as α-fetoprotein, carcinoembryonic antigen, and many others. They also express telomerase, a highly active enzyme characteristic of embryonic tissues. As noted previously (see Chapter 16), the ends of linear chromosomes in animals and humans contain thousands of highly conserved hexadeoxynucleotide repeats, -TTAGGG, known as telomeres. These allow the chromosome ends to attach to the nuclear envelope and prevent their degradation and recombination. With each Replication, telomere length is shortened by approximately 128 Base Pairs. For dividing somatic cells, telomere shortening serves as a replicometer. Once telomeric sequences reach a critical size, cells lose their ability to divide, undergo senescence, and enter apoptosis (programmed cell death).

In tumor and embryonic tissues, telomerase extends the telomeres at the 3'-ends of chromosomal DNA and restores their original length following replication. The action of this enzyme halts cellular Aging, rendering the cells immortal.

C. Changes in Plasma Membrane Structure and Secretion

Cellular transformation leads to alterations in the Composition and Structure of oligosaccharide chains of Plasma Membrane Glycoproteins and glycosphingolipids, which in turn affects membrane permeability and charge. Specifically, the synthesis rate and structure of adhesion molecules and integrin receptors (see Chapter 5) present in tumor cell membranes are altered.

Secretion of certain proteases, collagenases, and glycosidases is observed; these enzymes degrade Collagen, proteins, and glycosaminoglycans of the Extracellular matrix, facilitating tumor invasion into neighboring tissues and Blood Vessels. Additionally, the synthesis of angiogenesis factors is upregulated, stimulating The Development of new blood vessels required to supply cancer cells with nutrients.

D. Role of Hormones and Growth Factors in Tumor Development

GROWTH AND DEVELOPMENT in both normal and tumor cell lineages are initiated by the action of growth factors (GFs). By interacting with cell-surface receptors or intracellular receptors, GFs stimulate a cascade of events within The Cell that lead to the activation of genes responsible for the synthesis of proteins necessary for Cell Growth and Division (Fig. 16-7).

Class="center">Fig. 16-7. The action of growth factors on the cell. GFs bind to receptors either on The cell membrane surface or intracellularly. A — GFs trigger protein phosphorylation either directly through interaction with receptor Tyrosine Kinases (IGF-1, IGF-2, Insulin) or by engaging adenylate cyclase or phosphatidylinositol cascades and activating protein kinases. Phosphorylated proteins activate Transcription factors that induce the synthesis of new mRNAs and proteins. B — The GF enters the cell and forms a complex with an intracellular receptor, translocating to the nucleus to activate the transcription of growth-stimulating genes. Genes encoding GFs (I), receptor proteins (II), signal transducers (III), and transcription factors (IV) are termed Proto-oncogenes. Upon structural alterations in I, II, III, or IV, proto-oncogenes become oncogenes and drive aberrant growth: 1 — G-protein; 2 — enzymes that synthesize second messengers: adenylate cyclase, phospholipase C, guanylate cyclase.

Evidently, if the genes encoding receptors, signal transducers, and transcription factors undergo Mutations that result in their constitutive expression, controlled growth is replaced by unrestrained proliferation.

In tumor cells, the Synthesis and Secretion rates of certain hormones and growth factors increase. Tumors acquire the capacity for autonomous growth by shifting to paracrine or autocrine MECHANISMS OF CELL growth regulation.

Under the autocrine mechanism of regulation, tumors synthesize growth factors and their receptors (GFRs), or oncoproteins that mimic GFs or GFRs. These molecules interact with one another to autostimulate cell growth and division.

Paracrine regulation involves the interaction of GFs produced by certain cells with GFRs located on neighboring cells. For instance, in Lung Cancer, stromal cells produce insulin-like growth factor II, which interacts with receptors on lung cancer cells, stimulating their growth and division.