1. Changes in glycosidation of lipids and proteins:
The Golgi complex plays a central role in the biosynthesis of gangliosides and other glycosphingo lipids. There is evidence that in cancer cells, there are surface membrane changes that involve a loss of glycosphingo lipids and these alterations are due to the reduction of one or more glycosyltransferases present in the Golgi Complex.
2. Changes in glycolysis and blood glucose utilization:
In many cancer cells, the allosteric regulation and interlocking coordination appear to be defective: glycolysis proceeds at higher rate than required by the citric acid cycle. As a result, cancer cells use far more blood glucose than normal cells, but cannot oxidize the excess pyruvic acid even in presence of O2. To reoxidize cytoplasmic NADH, most of the pyruvate is reduced to lactate. This is because of small number of mitochondria in tumor cells. In addition, some tumor cells overproduce an isozyme of hexokinase that is associated with the cytosolic face of the mitochondrial inner membrane and is insensitive to feed back inhibition by glucose 6-phosphate.
3. Changes in isozymes: The isozyme profile of cancer cells is close to the fetal pattern. In fetal stage, the aldolase isozymes are in the A and C forms, whereas, in adult, the isozymes are of B form. In cancer cell the isozyme B type is replaced by isozyme A as it is found in hepatomas in adult.
4. Synthesis of fetal proteins: ?-feto protein (AFP) and carcinogen embryonic antigen (CEA) are the proteins, which are normally synthesized by the fetal cells, but not in adult stages. But in cancer cells these two proteins have been found to be synthesized. CEA cane be found in liver and lung cancer and AFP can be found in liver and testicular cancers.
5. Enzyme alterations: Tumor cells often produce elevated levels of cell surface receptors specific for the proteins and polysaccharides composing basal lamina (e.g., collagen, proteoglycans and glycosaminoglycans) and secrete enzymes that digest many proteins. Many tumor cells also secrete a protease called plasminogen activator, which cleaves a peptide bond in the serum protein plasminogen, converting it to an active protease plasmin. Secretion of a small amount of plasminogen activator causes a large increase in protease concentration which penetrates and digests the basal lamina. Thus the tumor cells become metastatic.
6. Surface changes in cancer cells:
(a) In cancer cells, anoding mobility is usually higher than the normal owing to the increased number of negative charges, provided by a more abundant amount of glycosaminoglycans in the cell surface.
(b) Some cancer cells, show electrical uncoupling owing to the disappearance of gap junctions.
(c) In cancer cells, the receptor molecules on the cell surface tend to diffuse more easily within the lipid layer because, normally these are attached to microfilaments with the plasma membrane to prevent motility of the receptors.
(d) In cancer cell, the cell membrane glycolipids and glycoprotein contents are reduced. The amounts of gangliosides and enzymes for synthesis function are reduced. Normally cell comprises four types of gangliosides, viz. GM1a, GM1, GM2 and GM3. Tumor cell contains predominantly GM3 type.
(e) A loss of regularly occurring antigens coupled with the appearance of new antigens in tumor cells have been reported. In cells transformed by adenoviruses or papovaviruses, the T-antigen is always present. In Epstein-Barr virus-stimulated transformed cells, the EB-nuclear antigen is found to be present on the cell surface.
Usually tumor cells synthesize new antigens on the surface, which bring them to an immunity reaction against hosts immune system and by the mechanism of immunological surveillance, these cells are being eliminated and fail to survive. If this mechanism is failed, the tumors are formed.
7. Cancer cells and iron transport: The iron and metal ions are transported and deliver iron to the cells through transferrin, a glycoprotein present in blood plasma that binds to specific transferrin receptors on the cell membrane. After penetration inside, the iron binds to other proteins such as ferritin and is deposited for use in many enzymatic systems.
The cancerous cells, transformed by an oncogenic virus secrete a low molecular wt agent call siderophore like growth factor, which has a high capacity for binding iron (Chelating agent) and transporting it inside the cell (which acts as an ionophore). This siderophore growth factors are delivered to the medium where they bind the metals and competing with transferrin. They import metal ions by this alternative mechanism and compete with normal cells for essential metal ions and deprive them from metal ions.
8. Fibronectin and cancer cells: Fibronectin is a high molecular wt glycoprotein, occurs widely in connective tissues, and among others and it is thought to have a role in determining the distribution of cells within both embryonic and adult tissues. The presence of fibronectin increases cell adhesion to the substratum and the other cells and influences the morphology of the cell and inducing locomotion and migration.
Fibronectin; originally called LETS (large external transformation sensitive) protein. It is absent or drastically absent in cancerous transformations. The breaking up of this LETS protein causes the cell to invade tissues locally and to metastasize.
9. Disorganization of cytoskeleton:
Transformation also alerts the cytoskeleton and by immunoinflurescence or electron microscopy, it can be seen that both microtubules and microfilaments are disorganized, producing considerable changes in shape. The normal fibroblast cells, which appear star-shaped and flattened from the side are transformed into a rounded cell. In these cells, the microtubules are very short and are randomly oriented and the actin microfilaments are organized into stress fibres.
Transformed cells also display blebs over the surface. This is due to the disorganization of the microtubule and microfilaments. It is possible that a change in vinculin molecule produced by phosphorylation could lead to the detachment and disorganization of the actin molecule.
Molecular disorganization of cytoskeleton also disturbs the normal organization of cytoplasmic organelles, particularly Golgi bodies, centrioles, spindle fibres and endoplasmic reticulum in the cytoplasm.
10. Loss of anchorage dependence: The cancer cells can grow without attachment to the surface. This is an contrast to the normal cells, which firmly adhere to the surface. Alterations in the structure of a protein vinculin is said to be responsible for the loss of anchorage property in cancer cells.
11. Loss of contact inhibition: Normal cells growing in tissue culture tend to establish cell contacts by adhesion to neighbouring cells. At the point of adhesion, some kinds of electron dense plaques are formed in both contacting cells. At the same time, there is a slowing down of the amoeboid process, which results in contact inhibition of movement. In contrast, cancer cells are unable to form adhesive junctions and do not show this type of contact inhibition. Therefore, normal cell divides in the culture medium and form a monolayer, while, the cancer cells form multilayers and they pile up on the top of one another.