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Friday, February 8, 2013

Cancer Cell Anatomy

A cancer cell is characterized by: acceleration of the cell cycle; genomic alterations; invasive growth; increased cell mobility; chemotaxis; changes in the cellular surface; and secretion of lytic factors.

Morphologically, the cancerous cell is characterized by a large nucleus, having an irregular size and shape, the nucleoli are prominent, the cytoplasm is scarce and intensely colored or, on the contrary, is pale.

The nucleus of neoplastic cells plays through its changes a main role in the assessment of tumor malignancy. Changes concern its surface, volume, the nucleus/cytoplasm ratio, shape and density, as well as structure and homogeneity. Ultrastructural characteristics are related to nucleus segmentation, invaginations, changes in chromatin, such as heterochromatin reduction, increase of interchromatin and perichromatin granules, increase of nuclear membrane pores, formation of inclusions, etc.

The nucleolus is characterized by hypertrophy, macro- and microsegregation, its movement towards the membrane, numerical increase and formation of intranuclear canalicular systems between the nuclear membrane and the nucleolus.

Mitoses are characteristic of malignant cells. The number of mitoses increases, atypical mitosis forms with defects in the mitotic spindle appear, which results in triple or quadruple asters and dissymmetrical structures and atypical forms of chromosomes.

Nuclear changes explain the presence of different cell clones and genetic anomalies associated with these changes. In intensely anaplastic tumors, the presence of gigantic nuclei and multinucleate cells expresses abnormal divisions.

These morphological characteristics reflect the changes occurring at metabolic level, with the augmentation of structures in relation to cell division and the attenuation of structures associated to other metabolisms.

The cytoplasm also undergoes changes, new structures appear or normal structures disappear. The accumulation of ribosomal and messanger RNA in the cytoplasm makes it basophilic. Malignant cells have a small cytoplasmic amount, frequently with vacuoles.

The granular endoplasmic reticulum has the appearance of a simplified structure. Amorphous, granular of filamentous material can accumulate in the cisternae. Fragmentation and degranulation are frequently found, with the interruption of connections between the granular endoplasmic reticulum and mitochondria. Fingerprint like formations are not uncommon. The decrease of the granular endoplasmic reticulum from tumor cells occurs concomitantly with an increase of free ribosomes and polysomes, which shows an enhanced production of proteins necessary for the cell growth process.

The agranular endoplasmic reticulum is, during the initiation phase, hyperplastic, without being correlated with functional hyperactivity. In other malignancy phases, the endoplasmic reticulum undergoes a reduction.

The Golgi apparatus in malignant cells is generally poorly developed, which involves a positive correlation with the lack of tumor cell differentiation. The cells that have completely lost differentiation sporadically exhibit a Golgi apparatus.

Mitochondria decrease in volume with tumor development. Mitochondria show a high variability of shape and volume, and huge mitochondria can be sometimes observed. Abnormal glycolysis processes occur in mitochondrial membranes, known in the literature as the “Warburg phenomenon”. Changes in mitochondrial crystals occur, inclusions are present in the matrix, and pyknotic images can appear. The longitudinal distribution of mitochondria involves a cytochrome oxidase insufficiency.

Peroxisomes are only present in tumors formed by cells that normally contain these organelles, such as hepatocytes. It has been established that the number of peroxisomes from malignant cells is reversely proportional to growth speed and expresses the degree of differentiation loss.

Glycogen in high amounts is a characteristic of malignancy, especially in the liver and kidneys, but the already malignant cells generally contain a small amount of glycogen, as it has been found in hepatic and cervical carcinomas. The decrease of glycogen up to its disappearance parallels the increase of lipids.

Lysosomes undergo changes in the process of cell malignization. Thus, secondary lysosomes, myelinic structures and lipofuscin granules appear.

Degenerative cellular changes can be expressed by cytoplasmic inclusions. In some forms of neoplasms, apoptosis occurs, with the presence of apoptotic bodies.

Microfilaments, intermediate filaments and microtubules appear in different proportions, in malignant cells. The capacity of invasion and metastasizing of the cancerous cell depends on its possibility to move, which is ensured by the actin content.

Epithelial carcinomas contain cytokeratins, mesenchymal tumors contain vimentin, and in the central nervous system cells is an acid protein from glial fibers, with a special role in tumor diagnosis.

Cytostatics act by the depolymerization of tumor cell microtubules, which leads to the inhibition of the metastasizing capacity, as well as mitosis and tumor growth.

The cell membrane plays an extremely important role in the malignization process. Surface molecular changes, associated with malignization, are able to influence the evolution of a tumor, as well as the host reactions to the lesion. Proteins and carbohydrates that act as enzymes and as cell surface receptors can also undergo changes:
  • increase or diminution in the number of surface receptors, changing cell sensitivity to the regulating mechanisms of the host;
  • structural changes of proteins or surface receptors that no longer react with the corresponding ligand;
  • presence of new surface molecules, characteristic of the embryonic tissue, which are hidden at the surface of adult cells.
Abnormal surface molecules are able to act as antigens and are recognized by the mechanisms of humoral and cellular defense. Consequently, tumor cells are covered with immune complexes, which allows the complement to destroy the cells covered by antibodies and allows phagocytes to attack the opsonized cells.

Malignant cells change their enzyme content, such as the reduction of acid or alkaline phosphatase. Changes occur in the relation between sugars and the sialic acid from glycolipids and glycoproteins, and also the negative loading of the cell surface. The plasma membrane of malignant cell favors the accelerated transport of nutritive substances, especially sugars and amino acids.

The surface of malignant cells displays differentiation antigens that express a normal development of the cancerous cell and antigens specific for the tumor, which appear with the oncogenic transformation, by the change of the genetic program of the cell. The distribution of receptors in malignant cells is altered, which modifies the cell agglutination behaviour. On the cell surface there are specific surface proteases that are responsible for the agglutination capacity of cells under the action of plant lectins. By losing contact inhibition, tumor cells also acquire metabolic autonomy, both their proliferation and movement being favored.

On the surface of malignant cells, atypical microvilli, pseudopods and vesicles with extremely active enzymatic equipment appear.

Differences between cells from the periphery and the center of tumors have been found. The cell population from the center of the tumor has normal intercellular connections, with the presence of desmosomes and junctional complexes, while these are absent or reduced at the periphery. In areas with a high invasive rhythm, cells are completely detached from the tumor mass, and interconnections disspear altogether.

The presence of desmosomes and tight junctions facilitates the establishment of the epithelial origin of the neoplasm, while their absence indicates the mesenchymal origin.

Note: When a cell becomes cancerous, potassium which has high membrane permeability is pumped out of the cell and sodium enters the cell through the voltage gated ion channels making the inside of the cell potentially positive and the outside of the cell negative by comparison. Immune cells which carry a negative charge are repelled by the negative charge on the cell surface.

The basal membrane is present in benign tumors, while the invasive growth of malignant cells is characterized by fragmentation, reduplication or disappearance of the basal membrane. During the first phases of malignancy, defects are produced with the interruption of the lamina densa. Malignant cells have lytic factors that destroy the basal membrane.

The loss of the basal membrane is considered a fundamental criterion of morphological and biological differentiation between benign and malignant tumors. The basal membrane in malignant cells changes its structure or/and ratios between various components, such as: type IV collagen, laminin, heparan sulfate proteoglycan and fibronectin. Neoplastic cells secrete type IV collagenase that destroys type IV collagen, which facilitates metastasizing through the lysis of basal membranes from blood and lymphatic vessels. Thus, malignant cells are disseminated, but they can also leave the vessels and implant in other tissues and organs, with the formation ofmetastases.

In the process of destruction of the basal membrane, a special role is played by laminin and laminin receptors, receptors that are found in the cell membrane and are reorganized during invasive growth.

The functional changes of neoplastic cells cause the formation and elimination of active substances, such as: growth factors, hormones, molecules similar to hormones, lytic enzymes, etc. Lytic enzymes (collagenase, cathepsin and plasmogen activator) favor the increased mobility and dissemination of neoplastic cells.

Major alterations occur in energy metabolism, between normal and malignant cells, especially regarding the use of glucose. The energy production with the highest efficiency in cells is performed by glycolysis in the tricarboxylic acid cycle (TCA cycle of Krebs cycle), where 36 ATP molecules are produced for each glucose molecule. This metabolism is carried out by oxygen use and represents the main energy production pathway, in the majority of cells.

Cancerous cells exhibit anomalies of both glycolysis and the tricarboxylic acid (TCA) cycle. The cancerous cell is particularly characterized by a poor use of oxygen and the massive use of glucose, which is exclusively converted to lactic acid. Consequently, malignant cells take from blood a 5–10 fold glucose amount compared to normal cells and they produce a corresponding lactic acid amount that will be recycled and changed back to glucose in the liver.

Tumor cells behave like a metabolic parasite for the organism or they drain its energy.

Proliferation is the main characteristic of benign tumors and especially malignant ones. Cells grow continuously, without being submitted to the local or general control of the organism. Benign growth is maintained within certain limits, while malignant growth is invasive, with quiet phases, followed by intense and uncontrollable growth phases.

The cell cycle normally develops along four phases:
  • phase S, the cell synthesizes DNA, in order to prepare mitosis;
  • phase G2 follows immediately mitosis (phase in which the genome is equally distributed between the two daughter-cells). It occurs between DNA replication and cell division;
  • phase M or mitosis, characterized by the appearance of chromatids migrating separately between the two daughter-cells;
  • phase G1 is the time interval elapsed between the previous nuclear division and the beginning of DNA synthesis. This phase is very short for bone marrow cells and in enterocytes from intestinal crypts or, in other cases, it can be very long. Cancerous cells have an accelerated cell cycle.
In the case in which the division speed in a tumor is not accelerated, neoplastic proliferation is the result of a disorder in cell maturation, a great number of cells being able to divide within the tissue. In such tumors, a slowing down of the rhythm of cellular apoptosis has also been found, as it happens in lymphoid tumors.

Genomic alterations, a cancer initiating process, persist all through the evolution of a tumor. The combined action of alterations in the mitotic cycle, the deficient synchronization between the nuclear and cytoplasmic divisions and the alterations preceding the existence of the genome induce more and more the instability of cell lines. Aneuploidy, polysemy and chromosomal deficits cause extremely variable morphological and behavioral clones. The depression of some segments of the genome can also enhance the pleiomorphic aspect of neoplastic cells and explains their abnormal secretions.

The proliferation and migration of neoplastic cells from a tumor is unpredictable. The movement of neoplastic cells starts with the formation of irregular cytoplasmic pseudopods, which infiltrate through basal membranes. Between the differentiation grade of a tumor, on the one hand, and its invasive growth, on the other hand, there is a correlation, which means that differentiation processes inhibit the capacity of movement of the cell.

The active locomotion of a malignant cell involves the enzymatic dissolution of the surrounding host tissue, especially of the interstitial matrix. At the beginning of the invasion, a loosening of the interstitial matrix of the host tissue occurs, by the appearance of an edema. The edema is explained by a higher permeability of the capillaries and the lack of lymphatic vessels with a draining role inside and in the proximity of the tumor. The size of the interstitial fluid volume facilitates cell locomotion. With the invasive growth, the destruction of the host tissue, its real lysis occurs, which is partially caused by enzymatic processes, and partially by atrophy through the pressure exerted by the tumor tissue.

The invasion and infiltration of malignant cells is characterized by the fact that they leave the tumor tissue and penetrate the neighboring tissue. But this property is not only specific for malignant tumors, this can also be found in other cells, such as: granulocytes, osteoclasts, endothelial cells and trophoblastic cells. Unlike these cells, the invasive growth of malignant cells is a progressive and continuous growth, ending with the destruction of the host tissue.

The malignant cell that grows invasively has the capacity to move, to produce lytic factors and phagocytose the host tissue. It grows especially in preexisting spaces but it can also create new spaces, by the destruction of the surrounding tissue. Between cytokinases and the invading capacity of cells, there are negative correlations, the cells having in certain phases a proliferative behavior, and in other phases an invasive behavior.

Invading cells have a higher content of actinic filaments and they form plasminogen activator, collagenase, elastase and proteoglycan decomposing enzymes. Proteolytic enzymes are secreted by both malignant cells and certain cells of the host tissue, such as: endothelial cells, fibroblasts, macrophages, mastocytes and lymphocytes.

The hypothesis that lytic factors produced by malignant cells can also initiate the angiogenesis process is advanced.

The loss of differentiation of the malignant cell is an important component. A determining role in this process is played by the reduction of cell organelles, especially the endoplasmic reticulum (which synthesizes proteins) and the Golgi apparatus. The loss of polarity of cell organelles, as well as of some properties of the cell membrane, also occurs. Malignant cells morphologically and functionally become similar to the fetal cells of the host tissue.

In reality, malignant cell complexes are composed of three types of various cells, in which not only the loss of differentiation takes place, but also aberrant processes, along with normal ones, excessive maturation and synthesis of new substances. This explains the histological variety of the cell population of a tumor. Multidirectional differentiation explains the appearance of atypical substances; thus, neoplastic epithelial cells can produce collagen.

At ultrastructural level, the main characteristic is not the loss of differentiation and the simplification of malignant cell structures, but structural and functional reorientation.

The loss of differentiation can be explained by the reduction of the postmitotic regeneration time, which results in the diminution of the differentiation time. Genetic information defects can also be mentioned. These processes cause changes in the cytoplasmic composition and intermediate metabolism and glycogen anomalies.

The differentiation process differs from one tumor to another, and it can be characterized by:
  • the maintenance of certain structures and functions;
  • the appearance of new cell structures and functions;
  • the appearance of new structures, such as metaplasia and heteroplasia;
  • the appearance of differentiations;
  • the disappearance of functions in malignant cells such as anaplasia and cataplasia. Anaplastic tumor cells lose their specific structural characteristics, having small amounts of granular endoplasmic reticulum and some mitochondria.
It can be considered that there is no principle contradiction between malignancy and differentiation, and the loss of differentiation during malignization should be regarded as an epiphenomenon.
In a malignant cell population, subpopulations and subclones develop, which are distinguished in terms of invasiveness, aggressiveness and the capacity of metastasizing. The peculiarities specific for each neoplasm result from heterogeneity, the presence of subclones whose unpredictable appearance and variation, supplemented by the local reaction of the host tissue and of the organism, make difficult tumor therapy.

In addition to these peculiarities of tumor cells, the following should be considered: the relation of the tumor to the stroma; the different behavior regarding the invasion and metastasizing of the different subclones; the different structure of cells, in terms of antigenicity and/or membrane glycoproteins and the variable cell sensitivity to cytostatics, radiation, etc.

Cytostatic treatment should aim to eliminate malignant subpopulations, since these have a high proliferation and invasion capacity. It should be mentioned that only a small part of the tumor cells that reach blood circulation have metastatic properties, and only when they find favorable conditions.

Depending on the metastasizing subclone, the cellular structure of metastases is similar or different, compared to the primary tumor.

The involvement of the host tissue in the development of a tumor is strongly expressed by the growth rhythm and the possibilities of tumor metastasizing. The reactions of the host tissue are initiated by immunological and non-immunological mechanisms  . The invasive cell acts on the extracellular matrix of the host tissue, in particular on collagen and elastin.

This action develops along three successive stages. In a first stage, the receptors of the tumor cell membrane bind to the glycoproteins of the host tissue, especially laminin and fibronectin. In the second stage, tumor cells secrete hydrolytic enzymes that stimulate the secretory activity of host cells. In the third stage, the dissolution of the components of the host tissue matrix occurs, and desmoplasia of these components is stimulated.

According to Carr and Unerwood, 1974, tumor cells stimulate the following phenomena:
  • the lymphoreticular reaction, with the invasion of lymphocytes, macrophages, lymphoreticular cells, immunologically active cells;
  • the vascular reaction, with the proliferation of endothelial cells and the formation of new capillaries;
  • the fibrous reaction, with fibroblast proliferation and collagen deposition;
  • the inflammatory reaction, with polymorphonuclear infiltration (neutrophils and eosinophils).
During its development, the malignant tumor needs the host tissue to survive and to grow. As part of the non-immunological defense reaction, a special role is played by activated macrophages, which are tightly bound to T lymphocytes. Some biochemical mediators and chemical reagents are able to destroy tumor cells non-immunologically or to inhibit their growth. In the case of the regression of a tumor, the phagocytic and Killer activity of macrophages increases. Spontaneous regressions have been found in some neoplasms: melanomas, choriocarcinomas, neuroblastomas, hypernephromas, etc.

The immunological cellular response controls through its mechanisms the growth of malignant cells. Complex processes with specific and non-specific immunodepressive effects take place. Immunological factors are supposed to eliminate malignant cells rapidly, before the appearance of clinical manifestations.

Characteristics of benign/malignant tumors
Growth typeExpansiveInfiltrating
Growth speedSlow (in general)Rapid (in general)
StructureTypicalAtypical (dedifferentiation − anaplasia)
MitosesRare + TypicalNumerous + Atypical
EvolutionLocalLocal + General
Local consequencesVariable (compressions, ...)Severe (infiltration, destruction, necrosis, ...)
General consequencesNone (exceptions : secretory tumors or at particular sites)Constant + severe (in the generalization phase)
Spontaneous evolutionUsually favorableAlways fatal
Evolution after removalNo recurrencesCommon recurrences

The growth of a tumor depends on its vascularization. It has been found that poorly vascularized or even avascular tumors slow down their development or they even stop growing. In contrast, the appearance of capillaries, the infiltration of the tumor by a great numer of capillaries, stimulates tumor growth and proliferation. Malignant cells secrete some substances that stimulate the formation of new vessels, which are called by Bassermann (1984) the “tumor angiogenesis factor” (TAP).

Angiogenesis is a normal physiological response that appears in other processes as well, such as cicatrization and inflammation. TAP molecules are probably produced and elaborated by host cells, such as lymphocytes, macrophages, monocytes, etc.

Due to the fact that tumor cell proliferation occurs at a much higher speed compared to the formation of new capillaries, necrobiotic, necrotic and apoptotic processes take place in the tumor.

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