Tumorigenesis: The Formation of Cancer Cells

Cell division is a physiological process that occurs in almost all tissues and under many circumstances. Under normal circumstances, the balance between proliferation and programmed cell death (usually mediated by apoptosis) is maintained by tightly regulating both processes to ensure the integrity of organs and tissues. It is now' accepted that cancer is a genetic disease resulting from changes to DNA sequence information in one or more genes, or from more profound structural changes such as chromosomal translocations.

Cancer involves re-occurring modification of the genome of cells brought about by both internal and external (e.g., environmental) factors. This process of tumorigenesis was first uncovered by the discovery of mutated genes in cancer cells with either dominant gain of function (knowm as oncogenes) or recessive loss of function in tumor suppressor genes.

It is now understood that tumorigenesis is a multistep process, w'ith each step reflecting genetic changes that promote the progressive transformation of healthy cells into tumor cells (Figure 1.5). Many studies have shown that the genes of tumor cells are often modified at many different sites, ranging from disruptions as subtle as point mutations (i.e., one DNA base-pair change) to more obvious abnormalities such as chromosomal translocations in which a section of one chromosome moves to another chromosome. Furthermore, in the laboratory it can be demonstrated that the transformation of cancer cells growung in culture is multistep, with cells derived from mice or rats requiring at least tw'o genetic modifications to transform them, and with human cells requiring even more. Based on these observations, it has been proposed that tumor

Diagram showing the rnultistep formation of a tumor from normal cells

FIGURE 1.5 Diagram showing the rnultistep formation of a tumor from normal cells.

development occurs through a process similar to Darwinian evolution, in which a sequence of genetic modifications, each providing a different type of growth advantage, leads to the progressive change of healthy cells into tumor cells.

Weinberg and Hanahan and others have proposed a set of rules that rationalize the transformation of healthy cells into tumor cells. These rules postulate a defined number of cellular or biochemical characteristics (so-called acquired or hallmark traits) that are common to most and perhaps all types of human cancers. Weinberg and Hanahan have suggested that the large catalog of known tumor cell genotypes may result from ten essential modifications to cell physiology (Figure 1.6 A). These researchers have also suggested that the need for a cell to acquire all of these traits prior to complete transformation may explain why tumor cell formation is relatively rare during the average human life span. The most significant hallmarks are described below' in more detail.

Sustaining proliferative signaling: Cancer cells acquire self-sufficiency in growth signals to reduce their dependence on biochemical stimulation from their environment. For example, some cancer cells acquire the capacity to synthesize grow'th factors to which they respond.

Evading growth suppressors: This characteristic is commonly acquired by cancer cells. For example, some cancer cells escape the cell cycle into the quiescent state (G0), where they become insensitive to extracellular antigrowth signals.

Resisting cell death (apoptosis): The ratio between the rate of cell proliferation and the rate of cell attrition (mainly due to apoptosis) defines the ability of cancer cells to proliferate. Therefore, evasion of apoptosis is required for a tumor to expand in size.

Enabling replicative immortality: Although the first three characteristics described above are important for a cell to proliferate despite normal signaling controls, cell culture experiments demonstrate that cells need to overcome senescence and develop the characteristic of replicative immortality in order to develop into a tumor. This is normally achieved through overexpression of the telomerase enzyme to maintain telomere length.

Inducing and sustaining angiogenesis: As oxygen and nutrients are essential for cell survival (and waste products must be removed), each cancer cell needs to be within approximately 100 pm of a capillary blood vessel. Therefore, in order to progress beyond a critical size, tumors must induce and sustain the growth of new blood vessels through angiogenesis.

Activating invasion and metastasis: Approximately 90% of cancer deaths are caused by metastatic disease. Tissue invasion and metastasis enable cancer cells to leave the primary tumor site and colonize different parts of the body, leading to a tumor burden that eventually becomes untreatable.

De-regulating cellular energetics: In order to proliferate, cancer cells also need to adjust their energy metabolism. Cancer cells can reprogram their energy production from the normal aerobic metabolism of glucose to glycolysis, a process w'hich can be more favorable in the hypoxic conditions often found at the center of tumors. Moreover, the diversion of intermediates generated by glycolysis into various biochemical pathways may facilitate the biosynthesis of tumor- promoting macromolecules and organelles.

Avoiding immune destruction: In order to be able to expand into a tumor, cancer cells must avoid detection and destruction by the immune system. They use a number of mechanisms to achieve this, including the expression of ligands such as PD-L1 and CD80 on their cell surface which interact wnth receptors on immune cells (e.g., T-cells) to reduce their activity.

A. The “hallmarks” of cancer; B. Four of the hallmarks are considered to be either “emerging” or “enabling”

FIGURE 1.6 A. The “hallmarks” of cancer; B. Four of the hallmarks are considered to be either “emerging” or “enabling”.

Genome instability and mutation: To acquire the multiple hallmarks of cancer, cells must undergo a succession of genetic alterations. These genomic instabilities and mutations are made possible by increasing the rate of mutation through mechanisms such as increasing the sensitivity to mutagenic agents or by reducing the efficiency of genome maintenance systems, including DNA repair enzymes.

Tumor-promoting inflammation: There is growing evidence that the process of inflammation promotes tumorigenesis by supplying molecules such as growth factors and facilitating angiogenesis. Therefore, tumor cells up-regulate various signaling pathways associated with inflammation.

Of the ten hallmarks listed above, in their 2011 publication Weinberg and Hanahan regard both genomic instability and mutation, and tumor-promoting inflammation, as “enabling” characteristics because they are both involved in tumor progression rather than transformation (Figure 1.6 B). Similarly, the deregulation of cellular energetics and the avoidance of immune destruction are regarded as “emerging” hallmarks because not a lot of evidence has accumulated regarding their significance in relation to tumor initiation and progression.

There is growing evidence that the hallmarks of cancer described above are brought about by just two to three rate-limiting mutations. This may involve genes relating to DNA repair, cell-cycle checkpoint control, apoptosis, or chromosome integrity, and could cause the appearance of a small neoplasm or pre-neoplasm with a mutator phenotype that enables it to rapidly accumulate additional genomic changes in its cells, which then facilitates invasion and dissemination. An alternative hypothesis is that a mutator phenotype is not strictly necessary for oncogenesis. For example, if the two to three rate-limiting events provide a sufficient selective advantage in growth to enable clonal expansion to 106-107 clonogenic cells, then the effective mutation rate per unit time for the expanding clone, even at the normal mutation rate per cell division, is sufficient to enable a small neoplasm or pre-neoplasm to accumulate numerous additional genomic changes in a non-rate-limiting manner. Consequently, human age- incidence data which implies the existence of two to three rate-limiting events is consistent with both the original ten hallmark characteristics of cancer described by Hanahan and Weinberg, and with the identification of tumors with large numbers of mutations observed in recent sequencing studies. This two-phase model of oncogenesis corroborates other studies which suggest that introduction of three genes encoding the SV40 large-T antigen, the telomerase catalytic subunit, and an H-R AS oncoprotein into primary human mammary epithelial cells results in cells that form tumors when transplanted into immunocompromised mice.

The ability to study human tumors at the biochemical and genetic levels has undergone dramatic changes during the last 10 years (e.g., DNA arrays, genome sequencing, proteomics, etc.) and is likely to benefit from further developments in the future at an increasingly rapid pace. At present, the ability to understand a newly diagnosed tumor in terms of its genetic defects remains in its infancy. In the future, the evaluation of all somatically acquired DNA modifications in the genomes of tumor cells in biopsy material from cancer patients is likely to become common practice, followed by the use of highly targeted therapeutic agents (see Chapter 6). However, although the new era of targeted therapies is encouraging, even the best targeted agents eventually lead to resistance and tumor regrowth due to further genetic mutations and adaptions. One way around this problem would be to treat a tumor with a cocktail of agents designed to target each mutation, either in parallel or sequentially.

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