What does replicative immortality mean?
Normal human cells can grow and divide only a limited number of times, and undergo planned death (apoptosis) when they become old, damaged, or no longer needed. Cancer cells, due to genetic mutations which enable them to progress through the cell cycle despite DNA damage, replicate infinitely and evade apoptosis; and in effect, achieve replicative immortality (until the host dies).
What is cancer targeted therapy?
Targeted therapy is a specialized cancer treatment with medications that disrupt cellular mechanisms which cause or promote the growth and proliferation of cancer cells. Targeted therapies do not directly kill cancer cells, but alter their biological composition and inhibit their growth.
Targeted therapies are of two types:
- Small molecule inhibitors: Minute organic compounds that attach to the cancer cell surface or get right into the cells and interfere with their activity.
- Monoclonal antibodies: Lab-produced cancer-specific antibodies which attach to the cancer cell surface and activate the immune system.
What is cancer?
Cancer is a large group of diseases that results from unrestrained proliferation of a single type of cell which becomes abnormal due to genetic mutations. Genetic mutations are caused by faulty DNA copying (transcription), often inherited, sometimes due to environment factors or certain viral infections, but sometimes for no discernible reason.
Mutations in the genes responsible for regulation of growth and development give rise to the genes with a potential for cancer (oncogenes). One mutation leads to another, and gradually, the accumulation of mutations transforms a normal cell into a cancer cell. Cancer cells grow when they mustn’t, and don’t die when they must.
How does cancer grow?
Cancer cells grow by the same process that normal cells do, but far more rapidly and infinitely. The mutations in the cancer cells give them the ability to overcome the checks and balances that govern normal cell growth. At each stage of growth, cells go through a sort of chemical checkpoint that will stop growth from proceeding unless they satisfy necessary molecular conditions.
The genetic material inside the human cell consists of 23 pairs of chromosomes containing DNA, proteins, and genes that encode the growth and function of each cell. The DNA is inside the nucleus of the cell which floats in cellular fluid known as cytoplasm bound by a cell membrane. The cytoplasm also contains various proteins and organelles such as mitochondria, essential for the cell’s functioning and metabolism.
A normal cell cycle consists of the following four stages:
- Gap1 (G1): G1 is the first stage when, stimulated by growth factors; a cell grows in size and prepares for DNA replication. At this stage a regulatory mechanism known as G1/S Checkpoint monitors the microenvironment and will halt growth if any inhibitory signals are present.
- Synthesis (S): This is the stage when the DNA replication takes place. The G1/S Checkpoint checks the DNA for damage and initiates repair if the damage is repairable or triggers programmed cell death (apoptosis). DNA replication is completed if no damage is detected.
- Gap2 (G2): During G2 stage the cell continues to grow and G2/M Checkpoint checks to make sure the replicated DNA has no errors or damage. The cell proceeds to the next stage only if the G2/M Checkpoint detects no errors.
- Mitosis (M): During mitosis, cellular structures known as spindles form and pull the duplicated chromosomes apart into two exact replicas to form two daughter cells.
Three alternatives exist for the daughter cells depending on specific conditions:
- Continue to grow and divide further.
- Become quiescent in G0 (zero) stage retaining the ability to divide upon receiving growth signals.
- Mature and differentiate into a cell with a specific function and enter post-mitotic stage where they can no longer divide.
Genetic mutations in the cancer cells make these checkpoints malfunction and allow them to divide despite the presence of damage in their DNA. Cancer cells develop resistance to growth inhibitory and apoptosis signals, keep replicating and growing to the detriment of healthy cells.
What therapies target limitless replication in cancer?
Targeted therapies for halting limitless replication in cancer revolves around interfering with the cell cycle progression in cancer cells. Several small molecule drugs targeting the cancer cell’s limitless replication have entered the clinical trial stage:
Anti Telomerase agents
Each time a cell divides, it loses a fragment of the DNA strands. In order to prevent loss of vital information, the ends of the chromosomes have extra DNA material with a repetitive sequence, known as telomeres. Telomeres have no coding function. Telomeres act like protective caps on the ends of the chromosomes to prevent DNA erosion and DNA end-to-end fusions.
With each division of cells, the telomeres get a little bit shorter in normal cells, which is one reason for aging, as well. When the telomeres get too short to prevent loss of essential DNA from the chromosome, the cell initiates apoptosis.
Except for fetal cells and stem cells, normal cells, once mature, replicate mostly during wound healing and have sufficient telomere length to last a lifetime. Cancer cells grow and divide rapidly, so loss of telomeres can lead to DNA damage and halt their progress.
Stem cells and fetal cells produce an enzyme known as telomerase to add telomere length during growth and development. Telomerase also plays a role in DNA repair. Cancer cells activate a catalytic subunit of telomerase, known as human reverse transcriptase telomerase (hTERT), and a multiprotein complex known as shelterin, which help them maintain their telomere length.
Currently, the first antitelomerase agent targeting cancer cell’s telomerase activity has entered clinical trials.
Cyclins and cyclin-dependent kinases (CDK) are two classes of proteins that activate each of the four phases of cell cycle. CDK by themselves are inactive and cyclins bind to CDKs to activate them. Each phase of cell cycle has to be activated by a specific cyclin/CDK complex to complete the necessary process for growth, and progress past the checkpoint to the next stage.
Cyclin/CDKs inhibit the activity of an important growth inhibiting protein known as retinoblastoma, a tumor suppressing protein. Retinoblastoma protein binds to proteins known as E2 factors (E2F) and suppresses DNA transcription.
Small molecule drugs that inhibit the different cyclin/CDK protein complexes at different cell cycle stages, are in clinical trials.
The checkpoint mechanism is regulated by two proteins known as Checkpoint kinases (CHK1 and CHK2), which are involved in recognition of DNA damage and initiation of repair or apoptosis. Dysfunction in the checkpoint mechanism causes the CHK proteins to allow the cancer cells to progress in the cell cycle despite defects.
The mitotic (M) phase in the cell cycle is a complex process where a complete copy of the whole genome is precisely segregated and pulled apart by spindles into two identical daughter cells. The different proteins that regulate this process include:
- Plk1 to Plk3 (pololike kinases)
- NimA-related protein kinases (Nek2)
- Auroras (A, B and C)
Auroras are mitotic kinases (MTKs) that play a critical role in the precise separation of the daughter cells. Cancer cells have an excessive presence of Auroras which cause spindle defects and imperfect segregation, leading to malignant transformation of the cell.
Pololike kinases (Plks) play a role in cell division and checkpoint regulation during mitosis. Pololike kinases have been found to be abundant in many cancers. Small molecule drugs that inhibit the activity of MTKs and Plks, and induce apoptosis, are in early stages of clinical development.
Kinesin spindle proteins are responsible for the formation of spindles and proper division of the daughter cells. Blocking kinesin activity leads to cell cycle arrest and apoptosis. Kinesin inhibitors are in phase II clinical trials.
Normal cells have pathways to repair the DNA when strand breaks or mismatches occur. Poly ADP-ribose polymerases (PARP) are a family of enzymes which open up the damaged DNA to allow access to the components that repair the damage. The PARP enzyme becomes inactive after the repair, and if repair is not possible apoptosis takes place.
In cancer cells, the repair pathways are disrupted and the cells are resistant to apoptosis. PARP inhibitors can prevent repairs of DNA breaks in cancer cells and allow the breaks to pile up, which can enhance apoptosis signals. PARP inhibitors can be used as monotherapy in certain cancers with inherited repair/apoptosis deficiency (BRCA1 or BRCA2 gene mutations), or in combination with chemotherapy or radiation.
PARP inhibitors are in early stages of clinical trials.
Some targeted cancer therapies aim to stop replicative immortality in malignant tumor cells. Normal human cells can grow and divide only a limited number of times, and undergo planned death (apoptosis) when they become old, damaged, or no longer needed. Cancer cells, due to genetic mutations which enable them to progress through the cell cycle despite DNA damage, replicate infinitely and evade apoptosis. They achieve replicative immortality (until the host dies).
Multimedia: Slideshows, Images & Quizzes
Understanding Cancer: Metastasis, Stages of Cancer, and More
Learn the basics about cancer including types, causes, how it spreads, symptoms and signs, stages and treatment options. Read...
Signs of Cancer in Women: Symptoms You Can't Ignore
Colon and stomach cancer symptoms can surprise women but can be treated if detected early. Learn about breast cancer signs and...
Top 10 Cancers Quiz
Take this quiz to learn the causes of cancer. Get the facts about the causes, symptoms, and treatments for the world's most...
Cancer: Does This Cause Cancer?
Everything gives you cancer, right? Not really. WebMD's slide show tells you about the research into cancer and cell phones,...
Cancer: Symptoms of Common Cancers in Men
Can men get breast cancer? Cancer symptoms men need to watch out for include skin changes, difficulty swallowing, rapid weight...
Related Disease Conditions
Cancer is a disease caused by an abnormal growth of cells, also called malignancy. It is a group of 100 different diseases, and is not contagious. Cancer can be treated through chemotherapy, a treatment of drugs that destroy cancer cells.
Cancer Risk Factors and Causes
Though it's difficult to say why some people develop cancer while others don't, research shows that certain risk factors increase a person's odds of developing cancer. These risk factors include growing older, family history of cancer, diet, alcohol and tobacco use, and exposure to sunlight, ionizing radiation, certain chemicals, and some viruses and bacteria.
At What Stage of Cancer is Chemotherapy Used?
The decision to use chemotherapy may vary depending on the aggressiveness, stage and type of cancer. Usually, chemotherapy may be used for all stages in most cancer types. Chemotherapy is a type of medicine or combination of medications that is used to treat or kill cancer cells.
What Type of Cancer Makes You Very Tired?
Extreme and recurrent tiredness is one of the common symptoms of most types of cancers. Tiredness is usually considered a warning sign of cancer progressing. Tiredness related to cancers usually does not get better with adequate rest or sleep.
Can a Bronchoscopy Detect Cancer?
If there are any abnormal areas detected on tests such as an x-ray or CT scan, the bronchoscope can be used to collect a biopsy sample the labs can test for cancer.
Which Is the Deadliest Cancer?
Lung cancer is considered to be the most deadly cancer. More people die from lung cancer each year than from breast, colorectal and prostate cancer combined.
Cancer pain is a common experience that may result from the disease, treatment, or diagnostic procedure. Check out the center below for more medical references on cancer, including multimedia (slideshows, images, and quizzes), related disease conditions, treatment and diagnosis, medications, and prevention or wellness.
What Are the Top Ten Cancers?
Lung cancer is the number one killer cancer in the world. It is the most common cause of cancer-related deaths in both men and women.
Treatment & Diagnosis
- Cancer FAQs
- Cigar Smoking ... Heart & Lung Disease & Cancer
- 5 Causes of Lung Cancer in Non-Smokers
- Stress and Aggressive Breast Cancer: Cause or Effect?
- Complementary and Alternative Cancer Treatments
- Weight Gain, Obesity & Cancer Risk
- 10 Cancer Symptoms That Men Ignore
- Stage IV Lung Cancer With ALK (Anaplastic Lymphoma Kinase) Rearrangement
Medications & Supplements
- Targeted Therapy: What Is Oncogenic Addiction in Cancer Cells?
- Targeted Therapy: What Are The 10 Hallmarks of Cancer?
- Targeted Therapy: What Is Apoptosis in Cancer Cells?
- Targeted Therapy: What Are Targeted Antiangiogenic Cancer Therapies?
- Targeted Therapy: What Are Invasion and Metastasis in cancer?
- Targeted Therapy: What Is the Function of A Tumor Suppressor Gene?
- Targeted Therapy: What Drugs Target the Tumor Microenvironment?
Prevention & Wellness
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.