Cancer biology

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

Deregulation of the cell cycle

One critical step in oncogenesis includes changes in genes that regulate cell growth and behavior so as to facilitate uncontrolled proliferation. The process of cell division is very similar in cancer and normal cells, but in many cases cancers exhibit loss of control of the cell cycle.

Cell cycle phases

The normal somatic cell cycle consists of two alternate phases.

  • S phase
    • DNA is replicated
    • Duration is 78 hours
  • Mitosis (M)
    • Cell division produces two daughter cells
    • Duration is one hour

Separating these are two phases where neither DNA synthesis nor cell division take place.

    • Between M and S
    • Variable duration
  • G2
    • Between S and M

Cells may become quiescent and nondividing by leaving the cell cycle at G. to enter a G0 phase. It is thought that cancer progenitor cells (also referred to commonly as cancer “stem cells”) are often in the G0 phase.

Many of the molecules that drive and regulate the cell cycle have been identified. One important group consists of proteins called “cyclins” that can propel cells through the cycle by the activation of cyclin-dependent kinases (CDKs).

Regulation of the cell cycle normally ensures that cells have precise control of DNA duplication and subsequent cell division, protecting against a loss of genetic information. A number of checkpoints exist within the cell cycle and are crucial in this protection of the normal genome. Mechanisms to detect DNA damage due to incomplete or inaccurate replication often result initially in cell cycle arrest.

Cell cycle control is essential to protect the integrity of normal genes.

G1–S transition

Exactly when a cell moves from G1 to S is tightly controlled to ensure survival, with factors such as cell size, metabolic state, growth factor availability, and DNA damage affecting whether a transition takes place.

The most important checkpoint in the cell cycle is the restriction point, just before entry into S phase. Passage through this checkpoint is regulated by a number of growth factors and a number of critical genes, including p53.

p53 plays a key role in maintaining genomic stability. Normal cells with DNA damage become arrested in G1 and undergo programmed cell deaths (apoptosis) under the control of this gene. p53 is the most commonly mutated gene in human cancer, which is not surprising because loss of control of genomic stability is a central feature of cancers.

  • p53 controls passage between M1 and S phase
  • “Guardian of the genome”
  • Most frequently mutated gene in human cancer

MYC is a transcription factor that regulates the expression of genes promoting proliferation. Burkitt’s lymphoma is a type of cancer caused primarily by amplification of the MYC gene, but many more common types of cancers also have amplification of the MYC oncogene. Interestingly, if MYC is amplified in a normal cell, apoptosis often results.

A second change decreasing normal cell checkpoints is required in most cells in order for MYC to increase proliferation without causing apoptosis.

Cell cycle in cancer

Cancer cells characteristically demonstrate abnormalities in cell cycle and its control. Key features include the following:

  • Uncontrolled proliferation with no physiological requirement
  • Length of S and M phases is normal
  • Short G1 phase
  • Failure of checkpoints to arrest cell cycle
  • Failure to trigger cell cycle arrest or programmed cell death in presence of damaged DNA
  • Genomic instability with accumulation of multiple gene mutations

Independence from external growth-promoting and growth-inhibiting signals

Many normal cells enter the cell cycle (or delay entering the cell cycle) through growth signals from their environment. Through either endocrine (signals from distant cells) or paracrine (signals from adjacent cells) mechanisms, normal cells have a host of membrane-bound, cytoplasmic, and nuclear receptors that detect and relay growth signals to the cells either stimulating or inhibiting initiation of the cell cycle. Independence from these external growth signals is a common feature of cancer cells.

Receptor tyrosine kinases (RT Ks) are membrane-bound proteins that relay growth signals. Members of this family of proteins commonly overexpressed in cancers include the following:

  • Epidermal growth factor receptor 1 (EGFR/Her1)
  • Her2/Neu
  • Insulin-like growth factor receptor (IGFR)
  • Vascular endothelial cell growth factor receptors (VEGFR)
  • Platelet-derived growth factor receptors (PDGFR)
  • Fibroblast growth factor receptors (FGFR)

Almost all cancers have constitutive activation of an RT K or downstream signaling member of an RT K pathway.

A paradigmatic example of how this mechanism is important in cancer oncogenesis includes small deletions of the EGFR gene encoding for the intracellular portion of the receptor. The subsequent change in the protein results in constitutive activation that is independent of any extracellular signals. These mutations have been found primarily in lung cancers, but similar activating mutations in other family members or other components of the pathways involved in sensing growth signals are found in most cancers.

Overall, changes in the sensing of external growth signals include

  • Constitutive activation of progrowth RT Ks
  • Inactivating mutations, deletion, or epigenetic silencing of growth-inhibiting factors
  • Self-production of growth-promoting factors (autocrine)
  • Constitutive activation of downstream members of growth-promoting signaling pathways

A paradigm of the last point, constitutive activation of downstream members of growth-promoting signaling pathways, includes activating mutations of the RAS oncogene. In normal cells, RAS is activated by RTKs when they detect growth-promoting factors. In many types of cancers, most notably colon, pancreatic, and lung cancers, a specific mutation of the RAS gene results in constitutive activation.

Limitless replication

Most cells undergo a limited number of replications before becoming terminally differentiated and eventually experiencing programmed cell death (called “apoptosis”). If human cells are grown in tissue culture with supportive media that provide all their nutritional and metabolic requirements, they will grow and proliferate for approximately 10 to 15 population doublings and then stop dividing and experience senescence, characterized by a nonproliferative, metabolically inactive cell.

During DNA replication and cell division, the ends of each chromosome become shorter in the daughter cells. It is thought that this progressive shortening eventually results in the loss of critical DNA sequence and senescence.

A protein complex referred to as “telomerase” is now known to protect the ends of each chromosome during cell division by replacing the lost ends with repetitive DNA sequence. Cancers have been shown to routinely overexpress telomerase, thus protecting them from progressive shortening of the chromosomes and facilitating effectively limitless proliferation. Although telomerase is most commonly found to be activated in cancers, approximately 15% of tumors use an alternative mechanism that remains poorly understood.

  • Telomerase protects the ends of the chromosome, replacing lost genetic material after each replication.
  • Most cancers have increased telomerase activity.
  • Alternative, as yet unknown, mechanisms exist to protect the ends of chromosomes.

Evasion of apoptosis

Apoptosis is the term that refers to programmed cell death and represents the natural end to most cells in the human body. Evasion from apoptosis is one mechanism by which normal cells can become transformed.

There are two basic apoptotic pathways. The intrinsic pathway generally results from cells sensing DNA damage or other internal stress and activating cytochrome c release from the cellular mitochondria with the subsequent activation of the apoptosome complex and a cascade of proteases called the “caspases.”

The extrinsic pathway is triggered by external signals such as TRAIL or CD95 ligand but also eventually results in activation of the caspases. Inhibition of the intrinsic apoptotic pathway and/or insensitivity to the extrinsic apoptotic pathways is critical to the development and progression of cancer cells.

Follicular lymphoma is a cancer that results from the overexpression of bcl-2 through a genetic translocation—the aberrant juxtaposition of two pieces of DNA generally located on different chromosomes or parts of chromosomes. In follicular lymphoma, the bcl-2 gene is placed adjacent to a gene that is generally expressed at much higher levels. As a result, bcl-2 is expressed at much higher levels and significantly decreases intrinsic activation of apoptosis.

Establishing angiogenesis

Without recruiting new blood vessels, the size and extent of a tumor is severely limited. The recruitment and development of blood vessels (angiogenesis) is a universal characteristic of cancer cells. Often, cancer cells will express factors promoting blood vessel growth. This has been observed in different laboratory experiments; when cancer cells are compared with normal cells, they more rapidly and robustly establish blood vessels.

Growth factors that can be used to recruit blood vessels include

  • Vascular endothelial growth factor (1 and 2)
  • Platelet-derived growth factor (α and β)
  • Fibroblast growth factor
  • Angiogenin 1 and 2

Kidney cancer, specifically clear-cell carcinoma, has historically been known to be highly vascular. In patients with familial clear-cell carcinoma and in sporadic clear-cell carcinoma, mutations in the von Hipple-Lindau (VHL) gene are found approximately 85% of the time. VHL normally acts to suppress the activity of a gene called hypoxia-induced factor 1α (HIF1α). When cells experience hypoxia, VHL releases HIF1α, which acts as a transcription factor and increases the expression of genes that encourage new blood vessel formation (VEGF and others). The mutations of VHL found in familial and sporadic renal cell carcinoma also result in the release of HIF1α and the constitutive activation of signals encouraging new blood formation.

Invasion and metastasis

Most patients who die from cancer die from complications due to the metastatic spread of cancer cells throughout the body. Together with all the characteristics discussed above, cancer cells are frequently found to have the following characteristics:

  • Anchorage-independent growth
  • Decreased cell-to-cell adhesions
  • Increased migration
  • Increased invasion

The process of hematogenous metastasis (i.e., spread through the blood system) involves the sequential task of migrating through the stromal tissue present in most cancers, entering a blood vessel, traveling through the blood without getting stuck in the lungs or killed by immune cells, adhering to endothelial cells at a remote site, migrating through the endothelium to exit the vascular system, and growing and dividing in a foreign environment. The well established propensity for specific cancers to commonly spread to specific sites (i.e., prostate cancer to bone) is best modeled by a “seed and soil” hypothesis in which features of both the cancer cell and the environment of the metastatic site likely contribute to the observed predilections.

Some molecular changes associated with metastasis include

  • Expression of matrix-metalloproteases
  • Decreased expression of E-cadherin
  • Alteration of specific integrin family member expression