Senescence and immortalization



You need to register on site.  Post will be published after being moderated


Senescence is the permanent exit of a cell from the cell division cycle, accompanied by morphological and biochemical changes characteristic of aging.

Immortalization is the ability of cell populations to undergo an unlimited number of cell divisions.



Normal mammalian somatic cells can proliferate only a limited number of times in vitro, and the maximum number is often referred to as the “Hayflick limit.” When this limit is reached, the cells undergo various morphological and biochemical changes suggestive of aging, so the process is referred to as senescence. Senescent cells can remain metabolically active for a long period of time, even though they have permanently exited from the cell cycle. Typically, they secrete inflammatory factors. Senescence is thus distinct from cell death (including apoptosis, necrosis and autophagy). It is also distinct from terminal differentiation, where cells also exit permanently from the cell cycle but undergo changes that allow them to perform  specialized normal functions.

Senescent cells have been extensively studied as an in vitro model of aging. In humans, cellular senescence appears to be a major barrier to the development of cancer.


It is not practicable to test whether cells are truly capable of continuing to divide forever, so cells are usually regarded as being immortalized if they have undergone many cell divisions (typically 100) beyond the Hayflick limit. Many cancers contain immortalized cells and some cancer-derived cell lines have been proliferating in vitro for many decades.

Relevance of senescence and immortalization to cancer

Although the Hayflick number may be quite large (e.g., fibroblasts from an adult may divide up to 40 times before they become senescent), in most situations it is not large enough to permit tumor formation. A tumor containing 240 cells would be big enough to be lethal, but there are two major reasons why 40 cell divisions does not result in a tumor of this size. The first is that cell death occurs at a very substantial rate within tumors, for reasons that include genetic instability (see chapters   on   chromosomal   instability   and microsatellite instability) and difficulties with blood supply (see chapter on Angiogenesis) that result in cell death. The second is that the genesis of a fully malignant tumor cell requires the accumulation of a number of critically important genetic changes. Most of these changes occur at random and provide a growth advantage to the nascent tumor cell. This process consumes many more cell divisions than a normal cell is able to undergo before it becomes senescent.

Consequently, senescence forms a major barrier to carcinogenesis in humans. A cell containing some of the genetic changes required for carcinogenesis will not usually be able to proliferate sufficiently to form a clinically significant tumor while the senescence barrier is intact. Human cells become immortalized at a very low frequency (so low, that no clear example has yet been found of a normal human cell undergoing immortalization spontaneously in cell culture), so immortalization is a rate-limiting step in human carcinogenesis. In contrast, mouse cells become immortalized spontaneously at a measurable frequency, and correspondingly, the probability of a mouse cell becoming malignant is many orders of magnitude higher than for human cells. The ability to suppress tumor formation is a major selective advantage for a long-lived species such as H. sapiens.

A cell division counting mechanism

The existence of a limit to the number of times a cell can divide implies that there must be a cell division counting mechanism. According to the telomere hypothesis of senescence, the counting mechanism is based on the progressive shortening of the ends of chromosomes (telomeres) that occurs with cell division. Telomeres form protective caps that prevent the cell recognizing the ends of chromosomes as double strand breaks and repairing them, for example, by fusing the ends to each other. They contain repetitive DNA (in all vertebrates, the repeat unit is a hexanucleotide, TTAGGG), which ends in a single-stranded G-rich tail.  Telomeres  are  able to fold back on themselves and form a loop structure (referred to as a “t-loop”) when the singlestranded telomere invades duplex telomeric DNA and anneals to the complementary strand, thus hiding the free single-stranded telomere end. Telomeric DNA is recognized by specific binding proteins, including TRF1 and TRF2 which bind to double-stranded telomeric DNA, and POT1 which binds to single-stranded telomeric DNA. The reasons for telomere shortening include the following. First, DNA replication depends on small  RNA  primers,  which  get  degraded  and replaced by DNA. However, there is no mechanism  for  replacing  the  terminal  RNA  primer required  for  lagging  strand  DNA  synthesis, which results in the template for the next round of DNA synthesis being shorter. This is known as the “end replication problem.” Second, there appears to be a 50–30 exonuclease that shortens the C-rich strand, which creates or increases the length of a single-stranded G-rich telomeric tail. Regardless of the exact mechanism of telomere shortening, eventually telomeres become so short that they trigger the cell to exit permanently from the cell cycle. In order for a cell to become immortalized, it must somehow prevent telomere  shortening.  In  most  cancers,  this  is achieved by the activity of an enzyme, telomerase, and in a minority, it is achieved by another mechanism referred to as alternative lengthening of telomeres (ALT).


The telomerase holoenzyme complex is normally expressed in cells of the germ-line. It is also found in some normal somatic cells, especially those that are required to undergo extensive proliferation, but at levels that are insufficient to prevent telomere shortening. Telomerase synthesizes telomeric DNA to replace the DNA lost during cell division. The essential subunits include an RNA molecule (TElomerase RNA; TER; encoded by a gene designated TERC, which is an abbreviation of TElomerase RNA Component) that acts as the template for synthesis of telomeric DNA, the reverse transcriptase catalytic subunit (TElomerase Reverse Transcriptase; TERT) that carries out the synthesis, and dyskerin (encoded by the DKC1 gene), a protein that binds to TER. Telomerase activity can be detected in some normal human somatic cells, especially cells in highly proliferative tissue compartments such as the bone marrow, skin, mucous membranes, and epithelia of the gastrointestinal tract (GIT), but not at sufficient levels to completely prevent telomere shortening. Telomerase has an important role in these tissues, because inherited mutations in any of the genes that encode one of the three telomerase components (TERT, TERC, or DKC1) result in a condition called dyskeratosis congenita which is characterized by premature failure of proliferative capacity in tissues such as the bone marrow, skin, and GIT. In contrast, at least 85 % of all cancers contain sufficient levels of telomerase to prevent telomere shortening, and the percentage is even higher in most types of carcinomas. Telomerase is often activated in cancers by mutations in the TERT promoter. If TERT expression is artificially switched on by genetic manipulation in normal cells, it is usually able to induce telomerase enzyme activity, because there is usually expression of the other telomerase subunits. This prevents telomere shortening, and in some types of human cells, this results in immortalization. Inhibiting telomerase activity in cancer cells may cause cellular senescence or cell death, so telomerase is an attractive target for the development of new anticancer treatments.

Alternative Lengthening of Telomeres (ALT) Some immortalized cell lines and cancers have no detectable telomerase activity and maintain their telomeres by alternative lengthening of telomeres (ALT). Overall, about 8–10 % of human tumors utilize ALT to prevent telomere shortening.   ALT is a recombinational mechanism in which  one  telomere  uses  another  telomere (or itself via looping back) as a template for synthesis  of  new  telomeric  DNA.  The  ALT mechanism depends on the activity of the MRN complex  which  is  known  to  be  involved  in homologous recombination. ALT is often activated in cancer cells by loss-of-function mutations in ATRX, a protein involved in intrinsic immunity and chromatin remodeling. Cells that maintain their telomeres by ALT characteristically have very heterogeneous telomere lengths, ranging  from  undetectably  short  to  extremely long. They also have substantial quantities of extrachromosomal telomeric repeat DNA that may be either linear or circular. Some of the circular DNA is partly single-stranded, with an intact C-rich strand and a gapped G-rich strand (referred to as C-circles). The presence of telomeric DNA and telomere binding proteins within PML bodies is highly characteristic of ALT-positive cells. Types of tumors where ALT is common include glioblastoma multiforme (the most common primary brain tumor in adults), osteosarcomas, and some types of soft tissue sarcomas such as malignant fibrous histiocytomas and liposarcomas.

Tumor suppressor genes

Immortalization is facilitated by loss of function of the p16INK4a or RB1 genes and the p53 gene. Loss of the normal function of these genes results in a significant, but finite, increase in cellular proliferative potential. This permits the accumulation of additional genetic changes and increases the probably that activation of a telomere maintenance mechanism will occur. Cells containing an inherited p53 mutation from individuals with Li-Fraumeni syndrome are the only type of human cells known to undergo immortalization spontaneously.

Clinical relevance

Treatments that reverse the immortal phenotype may be a useful form of cancer therapy. An attractive target is telomerase, but inhibitors of telomerase may need to be combined with inhibitors of ALT to prevent the emergence of drug resistance.


Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12:1133–1138.

Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705.

Pickett HA, Reddel RR (2015) Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nat Struct Molec Biol 22:875–80.

Reddel RR (2000) The role of senescence and immortalization in carcinogenesis. Carcinogenesis 21:477–484 Reddel RR (2014) Telomere maintenance mechanisms in cancer:   clinical   implications.   Curr   Pharm   Des 20:6361–6374.



Добавить комментарий

Войти с помощью: 

Ваш e-mail не будет опубликован. Обязательные поля помечены *