In spite of their diversity, human cancers share several fundamental properties (Table 1.3). Different cancers display each of these to different extents. Moreover, these properties may be acquired step by step and become evident at various stages during the progression of a cancer. Most of these properties individually are also found in other diseases and some are even exhibited during physiological adaptive responses. However, the combination of uncontrolled cell proliferation, altered differentiation and metabolism, genomic instability, and invasiveness with eventual metastasis is unique to and defines cancer.
Increased and autonomous cell proliferation: The most obvious property of tumors is growth beyond normal measures. In fact, the term 'tumor' when used in a broader sense designates every abnormally large structure in the human body, also including swellings or fluid-filled cysts. More precisely, then, cancers belong to those tumors caused primarily by increased cell proliferation, i.e. a permanent and continuing increase in cell numbers. Increased cell proliferation as such is also observed during tissue regeneration, adaptative tissue growth, and in some non-cancerous diseases. For instance, atherosclerosis can also with some right be regarded as a tumor disease. In general, an increased number of cells in a tissue is designated 'hyperplasia'. Extensive hyperplasia or hyperplasia with additional changes such as altered differentiation ('dysplasia') is considered a 'benign' tumor. Dysplasia often precedes malignant tumors and in such cases is regarded as a 'preneoplastic' change. Substantial alterations in the tissue structure and in particular the presence of tumor cell invasion define a malignant tumor or cancer (Table 1.4). The borderlines between hyperplasia, benign tumors, and cancer are often evident from microscopic or even macroscopic inspection, but in some cases additional criteria or markers have to be employed to make the distinction. Hyperproliferation in cancers is brought about by an altered response to exogenous growth regulatory signals (^6). On one hand, cancers are often hypersensitive to growth-stimulatory signals, and some cancers become largely independent of them. On the other hand, sensitivity to growth-inhibitory signals is usually diminished or abolished. Together, these altered responses result in the growth autonomy that characterizes cancers. Moreover, it typically increases during their progression.
Table 1.3. Characteristic properties of human cancers
Increased cell proliferation (often autonomous)
Altered cell and tissue differentiation
Immortalization (growth beyond replicative senescence)
Invasion into different tissue layers and other tissues (with disturbed tissue architecture)
Metastasis into local lymph nodes and distant tissues
Insufficient apoptosis: Cell proliferation in cancers may be caused by a combination of three factors: (1) The rate of cell proliferation is enhanced by an increase in the proportion of cells with an active cell cycle, i.e., a higher 'proliferative fraction', and/or by a more rapid transit through the cell cycle, together resulting in increased DNA synthesis and mitosis. (2) The rate of cell death is often decreased by relatively diminished apoptosis (^7). In some cancers, this is in fact the driving force for increased proliferation. In others, the rate of apoptosis is enhanced compared to normal tissue; but not sufficiently so as to compensate for the increase in mitotic activity. (3) In normal tissues, successive stages of differentiation are typically associated with progressively decreased proliferative capacity and/or with apoptotic death of the fully differentiated cells (^7.1). Thus, a block to differentiation is in some cases sufficient to confer an increased proliferation rate.
Altered differentiation: Many cancers consist of cells which resemble precursor cells of their tissue of origin and have not embarked on the normal course of differentiation, whereas others show properties of cells at intermediate stages of differentiation. Some cancers, however, do consist of cells with markers of full differentiation, with the crucial difference that they continue to proliferate. In these cancers, it is not difficult to identify the cell of origin, which is important for diagnosis. Many cancers, however, express markers that do not occur in their tissue of origin (^12.5). Frequently, cancer cells express proteins which are otherwise only found in fetal cells. Such proteins, e.g. carcinoembryonic antigen in colon carcinoma or alpha-fetoprotein in liver cancer are called 'oncofetal' markers. Other proteins expressed in cancers are never synthesized in the original cell type, e.g. 'cancer testis antigens' in melanoma and various peptide hormones in small cell lung cancer. This phenomenon is called 'ectopic' expression. Some cancers change their phenotype to resemble cells from a different tissue in a process called 'metaplasia'. One might think that this is a clear hallmark of cancer, but metaplasia occurs also in some comparatively innocuous conditions. Metaplasia can, in fact, precede cancer development, e.g. during the development of a specific type of stomach cancer (^17). In some other carcinomas, metaplasia may be a late event. Other changes of cell differentiation obliterate the original cellular phenotype so strongly that it can be difficult to distinguish from which primary site a metastasis
Table 1.4. Some basic definitions in oncology
Tumor grade any abnormal increase in the size of a tissue a tumor characterized by permanently increased cell proliferation, progressive growth, and invasion or metastasis a tumor lacking growth beyond a circumscribed region within a tissue a malignant tumor a malignant tumor a malignant tumor formed by cells of the hematopoetic cells and found in the blood a malignant tumor formed by cells of the lymphocyte cell lineage a solid malignant tumor formed from connective tissue (mesenchymal) cells a solid malignant tumor formed from cells of epithelial origin a benign tumor displaying a glandular structure a malignant tumor showing resemblance to glandular structures a measure of the physical extension of a (malignant) tumor a measure of the cellular and/or architectural atypia of a tumor also used for swellings, unusual for benign hypertrophy or hyperplasia corresponding to 'cancer' in everyday language preferentially used for (suspected or verified) systemic disease can be restricted to specific lymphoid organs often originated from gland tissue often originated from gland tissue different systems are in use, for different (and even the same) cancer types different systems are in use, for different (and even the same) cancer types originates. Two such 'generic' cell types are a small epithelial-like cell with a large nucleus to cytoplasm ratio and a spindle-shaped cell resembling a mesenchymal fibroblast. These cell types are end points of cancer progression in some carcinoma cases, typically found in aggressive cases and therefore also in metastases.
So, altered differentiation confers properties to cancer cells that are otherwise found in tissue precursor cells, fetal cells or cells of other tissues. Moreover, altered differentiation is also related to increased proliferation. As pointed out above, the control of proliferation and differentiation are intimately linked in normal tissues. The final stages of differentiation of many normal tissues are associated with an irreversible loss of replicative potential or even with cell death. This process is therefore called 'terminal differentiation' (^7.1). For instance, differentiated cells in keratinizing epithelia crosslink with each other, dissolve their nuclei, and become filled with structural proteins. This way, a steady state between cell generation and loss is maintained which breaks down, if differentiation fails in a cancer.
Altered metabolism: Cell proliferation, whether normal or abnormal, requires according changes in cell metabolism. Most evidently, DNA synthesis requires deoxynucleotides, so enzymes required for nucleotide biosynthesis, and specifically of deoxynucleotide biosynthesis, are induced and activated in proliferating cells. Further cell components such as membranes and organelles also need to be duplicated. For this reason, lipid biosynthesis is increased in cancer cells, likely because they cannot obtain enough fatty acids, phospholipids and cholesterol from lipoproteins supplied by the gut and liver. As a consequence, expression and activity of key enzymes like fatty acid synthase and hydroxymethylglutaryl-coenzyme A reductase are increased in cancer cells. Porphyrin biosynthesis is also often increased. As Warburg already noted in the 1930's, many tumor cells switch from aerobic to anaerobic glucose metabolism.
A key requirement for cell growth is increased protein synthesis, which is apparent at several levels by enhanced size and number of nucleoli, increased expression of transcription initiation factors and enhanced phosphorylation of ribosomal proteins. A particularly strong boost in protein synthesis may be required during invasion and metastasis (^9).
Overall, cancer growth poses an enhanced energy demand on the patient, which increases with the tumor load. Moreover, cancers release the waste products of their metabolism, such as lactate, with which the body has to cope. These are, unfortunately, only some of the systemic effects of cancers. Cancers also secrete enzymes and hormones that act on the host, some of which are toxic. In particular, cytokines like tumor necrosis factor a can elicit a general break-down of metabolic function with visible wasting, termed 'cachexia', and suppression of the immune system, thereby facilitating 'opportunistic' infections. Other tumor products, such as FAS ligand (^7.3), can damage sensitive organs such as the liver, and ectopically produced hormones can interfere with homeostasis. For instance, calcitonin production by small cell lung cancers may cause life-threatening variations in calcium levels. Such indirect disturbances of the body homeostasis by cancers, designated as 'paraneoplastic' symptoms, can be as problematic for the well-being and survival of a patient as the malignant growth per se.
Genomic instability: A clear distinction between cancerous and non-cancerous cell proliferation lies in genomic instability. Cancer cells as a rule contain multiple genetic and epigenetic alterations (^2). Polyploidy, an increase in the number of genomes per cell, can be ascertained by measuring cellular DNA content. Aneuploidy, i.e. a change in the number and structure of individual chromosomes, is revealed by cytogenetic methods. These aberrations are often already revealed upon microscopic observation of tumor tissues by altered size and shape of the nuclei in the cancer cells and aberrant mitotic figures. Other cancers remain diploid or nearly so, but contain point mutations and/or altered DNA methylation patterns.
As cancers progress, the numbers of alterations in their genome tend to increase. Therefore, cancers, even if outwardly homogeneous, usually consist of cell clones that differ at least slightly in their genetic constitution. The variant clones are continuously selected for those proliferating fastest, tolerating adverse conditions best, capable of evading immune responses, etc., with the best-adapted cell clone dominating growth (Figure 1.5). This variation becomes particularly evident during tumor treatment by chemotherapy which exerts a strong selection pressure for those cell clones carrying alterations that allow them to survive and continue to expand in spite of therapy.
Figure 1.5 Clonal selection model of cancer growth. Genomic instability in a cancer continuously creates novel clones from the initial tumor (left). These clones are selected according to their ability to proliferate in the face of hypoxia and immune responses, and to adapt at metastatic sites. One (right) or several clones may succeed.
Ilvnnxiii Immune response
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