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Sunday, August 24, 2025

Cancer treatment

From Wikipedia, the free encyclopedia
Treatment of cancer
A patient prepared for radiation therapy

Cancer treatments are a wide range of treatments available for the many different types of cancer, with each cancer type needing its own specific treatment. Treatments can include surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy including small-molecule drugs or monoclonal antibodies, and PARP inhibitors such as olaparib. Other therapies include hyperthermia, immunotherapy, photodynamic therapy, and stem-cell therapy. Most commonly cancer treatment involves a series of separate therapies such as chemotherapy before surgery. Angiogenesis inhibitors are sometimes used to enhance the effects of immunotherapies.

The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient. Biomarker testing can help to determine the type of cancer, and indicate the best therapy. A number of experimental cancer treatments are continuously under development. In 2023 it was estimated that one in five people will be diagnosed with cancer at some point in their lifetime.

The primary goal of cancer treatment is to either cure the cancer by its complete removal, or to considerably prolong the life of the individual. Palliative care is involved when the prognosis is poor and the cancer termed as terminal. There are many types of cancer, and many of these can be successfully treated if detected early enough.

Types of treatments

The treatment of cancer has undergone evolutionary changes as understanding of the underlying biological processes has increased. Tumor removal surgeries have been documented in ancient Egypt, hormone therapy and radiation therapy were developed in the late 19th century. Chemotherapy, immunotherapy and newer targeted therapies are products of the 20th century. As new information about the biology of good cancer emerges, treatments will be developed and modified to increase effectiveness, precision, survivability, and quality of life.

Surgery

Malignant tumours can be cured if entirely removed by surgery. But if the cancer has already spread (metastasized) to other sites, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.

Examples of surgical procedures for cancer include mastectomy, and lumpectomy for breast cancer, prostatectomy for prostate cancer, and lung cancer surgery for non-small cell lung cancer. The goal of the surgery can be either the removal of only the tumor, the entire organ, or part of the organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.

In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy. Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.

Surgery may be performed before or after other forms of treatment. Treatment before surgery is often described as neoadjuvant. In breast cancer, the survival rate of patients who receive neoadjuvant chemotherapy are no different from those who are treated following surgery. Giving chemotherapy earlier allows oncologists to evaluate the effectiveness of the therapy, and may make removal of the tumor easier. However, the survival advantages of neoadjuvant treatment in lung cancer are less clear.

Radiation therapy

Radiation therapy (radiotherapy) is the use of ionizing radiation to kill cancer cells and shrink tumors by damaging their DNA causing cellular death. Radiation therapy can either damage DNA directly or create charged particles (free radicals) within the cells that can in turn damage the DNA. Radiation therapy can be administered externally via external beam radiotherapy or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumor, and may also be used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radio sensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.

Radiation therapy can lead to dry mouth from exposure of salivary glands to radiation, resulting in decreased saliva secretion. Post therapy, the salivary glands will resume functioning but rarely in the same fashion. Dry mouth caused by radiation can be a permanent problem.

Chemotherapy

Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. Chemotherapy can be given in a variety of ways such as injections into the muscles, skin, artery, or vein, or it could even be taken by mouth in the form of a pill. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.

Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.

Since chemotherapy affects the whole body, it can have a wide range of side effects. Patients often find that they start losing their hair since the drugs that are combatting the cancer cells also attack the cells in the hair roots. This powerful treatment can also lead to fatigue, loss of appetite, and vomiting depending on the person.

The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation.

Targeted therapies

Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule drugs are targeted therapy drugs that are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib (Gleevec/Glivec) and gefitinib (Iressa).

Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.

Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.

Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors. In February 2019, medical scientists announced that iridium attached to albumin, creating a photosensitized molecule, can penetrate cancer cells and, after being irradiated with light, destroy the cancer cells.

High-energy therapeutic ultrasound could increase higher-density anti-cancer drug load and nanomedicines to target tumor sites by 20x fold higher than traditional target cancer therapy.

Targeted therapies under pre-clinical development as potential cancer treatments include morpholino splice switching oligonucleotides, which induce ERG exon skipping in prostate cancer models, multitargeted kinase inhibitors that inhibit the PI3K with other pathways including MEK and PIM, and inhibitors of NF-κB in models of chemotherapy resistance.

A systematic review published in Cochrane database found that targeted therapies significantly improve progression-free survival by 35 to 40% in metastatic or relapsed cancer. While the research points to promising clinical outcomes, there is still limited evidence on the long-term effects of targeted therapies in terms of overall survival, quality of life, and severe adverse events.

Immunotherapy

A renal cell carcinoma (lower left) in a kidney

Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Cancer vaccines to generate specific immune responses are the subject of intensive research for a number of tumors, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells. It gained FDA approval in 2010.

Allogeneic hematopoietic stem cell transplantation (usually from the bone marrow) from a genetically non-identical donor can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.

The cell based immunotherapy in which the patients own natural killer cells (NKs) and cytotoxic T cells are used has been in practice in Japan since 1990. NK cells and TCs primarily kill the cancer cells when they are developed. This treatment is given together with the other modes of treatment such as surgery, radiotherapy or chemotherapy and termed autologous immune enhancement therapy (AIET).

Immune checkpoint therapy focuses on two immune checkpoint proteins, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Under normal conditions, the immune system utilizes checkpoint proteins as negative feedback mechanisms to return to homeostasis once pathogens have been cleared from the body. In a tumor microenvironment, cancer cells can commandeer this physiological regulatory system to "put a brake" on the anti-cancer immune response and evade immune surveillance.[28] 2018 Nobel Prize in medicine is awarded to Dr. James Allison of University of Texas MD Anderson Cancer Center in U.S. and Dr. Tasuku Honjo Kyoto University in Japan for their contributions in advance of PD-1 and CTLA-4 immune checkpoint therapy.

Hormonal therapy

The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. Although the side effects from hormone therapy vary depending on the type, patients can experience symptoms such as hot flashes, nausea, and fatigue.

Angiogenesis inhibitors

Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors need to survive and grow. Continued growth allows the invasion of cells into neighbouring tissues, and metastasis into distal tissues. There are many approved angiogenesis inhibitors including bevacizumab, axitinib, and cabozantinib.

Flavonoids have been shown to downregulate the angiogenic stimulation of VEGF and Hypoxia-inducible factor (HIF) but none have reached clinical trials.

Exercise prescription

Exercise prescription is becoming a mainstream adjunct treatment for cancer, based on studies which show that exercise (compared to no exercise) is associated with reduced recurrence rates, improved mortality outcomes, reduction of side effects from traditional cancer treatments. Although it is uncertain whether improved outcomes with exercise are correlated or causative, the benefit-risk ratio of including exercise as part of cancer treatment is large, as exercise has further benefits (e.g. cardiovascular, mental health) without major risks, although there is a small risk of overuse injury if added too aggressively. Exercise physiologists and exercise medicine specialists can assist oncologists and primary care practitioners with exercise prescription in cancer patients.

Walking is usually an excellent exercise option as an adjunct cancer treatment.

Synthetic lethality

Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of one or both of the genes.

Cancer cells are frequently deficient in a DNA repair gene. (Also see DNA repair deficiency in cancer.) This DNA repair defect either may be due to mutation or, often, epigenetic silencing (see epigenetic silencing of DNA repair). If this DNA repair defect is in one of seven DNA repair pathways (see DNA repair pathways), and a compensating DNA repair pathway is inhibited, then the tumor cells may be killed by synthetic lethality. Non-tumorous cells, with the initial pathway intact, can survive.

Ovarian cancer

Mutations in DNA repair genes BRCA1 or BRCA2 (active in homologous recombinational repair) are synthetically lethal with inhibition of DNA repair gene PARP1 (active in the base excision repair and in the microhomology-mediated end joining pathways of DNA repair).

Ovarian cancers have a mutational defect in BRCA1 in about 18% of patients (13% germline mutations and 5% somatic mutations) (see BRCA1). Olaparib, a PARP inhibitor, was approved in 2014 by the US FDA for use in BRCA-associated ovarian cancer that had previously been treated with chemotherapy. The FDA, in 2016, also approved the PARP inhibitor rucaparib to treat women with advanced ovarian cancer who have already been treated with at least two chemotherapies and have a BRCA1 or BRCA2 gene mutation.

Colon cancer

In colon cancer, epigenetic defects in the WRN gene appear to be synthetically lethal with inactivation of TOP1. In particular, irinotecan inactivation of TOP1 was synthetically lethal with deficient expression of the DNA repair WRN gene in patients with colon cancer. In a 2006 study, 45 patients had colonic tumors with hypermethylated WRN gene promoters (silenced WRN expression), and 43 patients had tumors with unmethylated WRN gene promoters, so that WRN protein expression was high. Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). The WRN gene promoter is hypermethylated in about 38% of colorectal cancers.

There are five different stages of colon cancer, and these five stages all have treatment:

  • Stage 0, is where the patient is required to undergo surgery to remove the polyp (American Cancer Society).
  • Stage 1, depending on the location of the cancer in the colon and lymph nodes, the patient undergoes surgery just like Stage 0.
  • Stage 2 patients undergoes removing nearby lymph nodes, but depending on what the doctor says, the patent might have to undergo chemotherapy after surgery (if the cancer is at higher risk of coming back).
  • Stage 3, is where the cancer has spread all throughout the lymph nodes but not yet to other organs or body parts. When getting to this stage, Surgery is conducted on the colon and lymph nodes, then the doctor orders Chemotherapy (FOLFOX or CapeOx) to treat the colon cancer in the location needed (American Cancer Society). The last a patient can get is Stage 4.
  • Stage 4 patients only undergo surgery if it is for the prevention of the cancer, along with pain relief. If the pain continues with these two options, the doctor might recommended radiation therapy. The main treatment strategy is chemotherapy due to how aggressive the cancer becomes in this stage, not only to the colon but to the lymph nodes.

Symptom control and palliative care

Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. In general, doctors have the therapeutic skills to reduce pain including, chemotherapy-induced nausea and vomiting, diarrhea, hemorrhage and other common problems in cancer patients. The multidisciplinary specialty of palliative care has increased specifically in response to the symptom control needs for these groups of patients.

Pain medication, such as morphine, oxycodone, and antiemetics are drugs to suppress nausea and vomiting. These are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.

Cancer pain can be associated with continuing tissue damage due to the disease process, or the treatment (i.e. surgery, radiation, chemotherapy). There is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, However these are not usually the predominant etiologic factors in patients with cancer pain. Some patients with severe pain associated with cancer are nearing the end of their lives, but in all cases, palliative therapies should be used to control the pain. Issues such as the social stigma of using opioids and health care consumption can be concerns and may need to be addressed for the person to feel comfortable taking the medications required to control his or her symptoms. The typical strategy for cancer pain management is to get the patient as comfortable as possible using the least amount of medications possible, even if that means using opioids, surgery, and physical measures.

Historically, doctors were reluctant to prescribe narcotics to terminal cancer patients due to addiction and respiratory function suppression. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients. The World Health Organization also noted uncontrolled cancer pain as a worldwide problem and established a "ladder" as a guideline for how practitioners should treat pain in patients who have cancer

Cancer-related fatigue is a very common symptom of cancer, and there are a number of approaches put forward for helping with this.

Mental struggles/pain

Cancer patients undergo many obstacles and one of these includes mental strain. It is very common for cancer patients to become stressed, overwhelmed, uncertain, and even depressed. The use of chemo is a very harsh treatment causing the cells of the body to die. Physical effects like this do not only inflict pain but also cause patients to become mentally exhausted and want to give up. For a lot of reasons including these, hospitals offer many types of therapy and mental healing. Some of these include yoga, meditation, communication therapy, and spiritual ideas. All of these are meant to calm and relax the mind, or to give hope for the patients that may feel drained.

Insomnia

A common disorder experienced by people that have survived cancer treatments is insomnia. Almost 60% of cancer survivors experience insomnia, and if it is not treated properly it can have long term effects on physiological and physical health. Insomnia is defined as dissatisfaction with sleep duration or quality and difficulties initiating or maintaining sleep. Insomnia can heavily reduce one's quality of life. Cognitive behavioral therapy has been seen to reduce insomnia and depression for cancer survivors.

Muscle strength

Decreased muscle strength is a common side effect to many different cancer treatments. Because of this, exercise is very important especially in the first year after treatment. It has been shown that yoga, water exercise, and pilates can improve the emotional well-being and quality of life of breast cancer survivors.

Fatigue

Fatigue is an unrelenting feeling of physical and mental tiredness that cannot be traced back to activity levels. It is a very common experience in cancer survivors, with most patients reporting some level of fatigue before, during, and after treatment. The cause of the fatigue can be due to the cancer itself, but frequently it is medical interventions to treat the cancer – like chemotherapy, radiation, surgery, and hormone therapy – that cause the feelings of extreme tiredness. The exact processes behind cancer-related fatigue are unknown. However, evidence suggests that biological processes like inflammation and stress hormone disruption may play a role. In addition, pre-existing risk factors like a genetic predisposition, sleeping troubles, a pre-existing mood disorder, adverse childhood experiences, and low levels of physical activity are associated with increased levels of cancer-related fatigue.

Treatment options for cancer-related fatigue can be pharmacological or non-pharmacological. Medications like erythropoietin, stimulants, and antidepressants can be prescribed, but their efficacy is modest. Thus, non-pharmacological interventions are the preferred treatment for cancer-related fatigue. Aerobic exercise and psychosocial interventions like cognitive behavioral therapy and mindfulness show promise in reducing feelings of fatigue in cancer patients.

Hospice care

Hospice care provides palliative care at home, or in a dedicated hospice institution, for a person with an advanced illness termed as terminal. Untreated cancer will prove terminal, and sometimes a choice is made to forgo treatment and its unpleasant side effects, and opt instead for hospice care. Hospice care aims to provide support for the person's medical, emotional, social, practical, psychological, and spiritual needs.

Advance care planning (ACP) can help a person to decide for themself their future care wishes as they approach end of life. ACP helps adults at any stage of health to decide, and record in writing, their wishes for medical treatment preferences, and future wants, preferably as previously discussed with relatives or carers.

Research

Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.

A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.

Patients who take part may be helped personally by the treatment they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. At the same time, new treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit. There is no guarantee that a new treatment being tested or a standard treatment will produce good results. In children with cancer, a survey of trials found that those enrolled in trials were on average not more likely to do better or worse than those on standard treatment; this confirms that success or failure of an experimental treatment cannot be predicted.

Exosome research

Exosomes are lipid-covered microvesicles shed by solid tumors into bodily fluids, such as blood and urine. Current research is being done attempting to use exosomes as a detection and monitoring method for a variety of cancers. The hope is to be able to detect cancer with a high sensitivity and specificity via detection of specific exosomes in the blood or urine. The same process can also be used to more accurately monitor a patient's treatment progress. Enzyme linked lectin specific assay or ELLSA Archived 13 July 2011 at the Wayback Machine has been proven to directly detect melanoma derived exosomes from fluid samples. Previously, exosomes had been measured by total protein content in purified samples and by indirect immunomodulatory effects. ELLSA directly measures exosome particles in complex solutions, and has already been found capable of detecting exosomes from other sources, including ovarian cancer and tuberculosis-infected macrophages.

Exosomes, secreted by tumors, are also believed to be responsible for triggering programmed cell death (apoptosis) of immune cells; interrupting T-cell signaling required to mount an immune response; inhibiting the production of anti-cancer cytokines, and has implications in the spread of metastasis and allowing for angiogenesis. Studies are currently being done with "Lectin affinity plasmapheresis" (LAP), LAP is a blood filtration method which selectively targets the tumor based exosomes and removes them from the bloodstream. It is believed that decreasing the tumor-secreted exosomes in a patient's bloodstream will slow down progression of the cancer while at the same time increasing the patients own immune response.

Complementary and alternative

Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine and have not been shown to be effective. "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. CAM use is common among people with cancer; a 2000 study found that 69% of cancer patients had used at least one CAM therapy as part of their cancer treatment. Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments which have been investigated and shown to be ineffective continue to be marketed and promoted.

Special circumstances

In pregnancy

The incidence of pregnancy-associated cancer has risen due to the increasing age of pregnant mothers. Cancers may also be detected incidentally during maternal screening.

Cancer treatment needs to be selected to do least harm to both the woman and her embryo/fetus. In some cases a therapeutic abortion may be recommended.

Radiation therapy is out of the question, and chemotherapy always poses the risk of miscarriage and congenital malformations. Little is known about the effects of medications on the child.

Even if a drug has been tested as not crossing the placenta to reach the child, some cancer forms can harm the placenta and make the drug pass over it anyway. Some forms of skin cancer may even metastasize to the child's body.

Diagnosis is also made more difficult, since computed tomography is infeasible because of its high radiation dose. Still, magnetic resonance imaging works normally. However, contrast media cannot be used, since they cross the placenta.

As a consequence of the difficulties to properly diagnose and treat cancer during pregnancy, the alternative methods are either to perform a Cesarean section when the child is viable in order to begin a more aggressive cancer treatment, or, if the cancer is malignant enough that the mother is unlikely to be able to wait that long, to perform an abortion in order to treat the cancer.

In utero

Fetal tumors are sometimes diagnosed while still in utero. Teratoma is the most common type of fetal tumor, and usually is benign. In some cases these are surgically treated while the fetus is still in the uterus.

Society and culture

Racial and social disparities

Cancer is a significant issue that is affecting the world. Specifically in the U.S., 1,735,350 new cases of cancer, and 609,640 deaths were expected by the end of 2018. Adequate treatment can prevent many cancer deaths but there are racial and social disparities in treatments which has a significant factor in high death rates. Minorities are more likely to receive inadequate treatment while white patients are more likely to receive efficient treatments in a timely manner. Having satisfactory treatment in a timely manner can increase the patient's likelihood of survival. It has been shown that chances of survival are significantly greater for white patients than for African American patients.

The annual average mortality of patients with colorectal cancer between 1992 and 2000 was 27 and 18.5 per 100,000 white patients and 35.4 and 25.3 per 100,000 black patients. In a journal that analyzed multiple studies testing racial disparities when treating colorectal cancer found contradicting findings. The US Veterans Administration and an adjuvant trial found that there was no evidence to support racial differences in treating colorectal cancer. However, two studies suggested that African American patients received less satisfactory and poorer quality treatment compared to white patients. One of these studies specifically was provided by the Center for Intramural Research. They found that black patients were 41% less likely to receive colorectal treatment and were more likely to be hospitalized in a teaching hospital with less certified physicians compared to white patients. Furthermore, black patients were more likely to be diagnosed with oncologic sequelae, which is a severity of the illness in result of poorly treated cancer. Lastly, for every 1,000 patients in the hospital, there were 137.4 black patient deaths and 95.6 white patient deaths.

An article in a breast cancer journal analyzed the disparities of breast cancer treatments in the Appalachian Mountains. African American women were found to be three times more likely to die compared to Asians and two times more likely to die compared to white women. According to the study, African American women are at a survival disadvantage compared to other races. Black women are also more likely to receive less successful treatment than white women by not receiving surgery or therapy. Furthermore, the US National Cancer Institute panel identified breast cancer treatments, given to black women, as inappropriate and not adequate compared to the treatment given to white women.

From these studies, researchers have noted that there are definite disparities in the treatment of cancer, specifically who has access to the best treatment and can receive it in a timely manner. This eventually leads to disparities between who dies from cancer and who is more likely to survive.

The cause of these disparities is generally that African Americans have less medical care coverage, insurance and access cancer centers than other races. For an example, black patients with breast cancer and colorectal cancer were shown to be more likely to have Medicaid or no insurance compared to other races. The location of the health care facility also plays a role in why African Americans receive less treatment in comparison to other races. However, some studies say that African Americans do not trust doctors and do not always seek the help they need and that this explains why fewer African Americans receive treatment. Others suggest that African Americans seek more treatment than whites and that it is simply a lack of the resources available to them. In this case, analyzing these studies will identify the treatment disparities and look to prevent them by discovering potential causes of these disparities.

Public perception

Despite recognition of improvements in outcomes, visceral fear of the disease is ubiquitous, and people may have to struggle to control it.

Among lung cancer patients, stigma, shame, social isolation, and discrimination are common. Such patients are sometimes told that they deserve cancer because of their smoking. Those patients also may have feelings of guilt for having cancer. Stigma in cervical cancer was predominantly driven by fear of social judgment and rejection, self-blame, and shame, with notable negative influences from gender and social norms, as both human papillomavirus infection and cervical cancer were stigmatized due to the perception that they arise from reckless behavior such as having multiple sexual partners or neglecting screening. Resilience may be a potent protective mechanism against stigmatization. Resilience in context of cancer treatment is patient's physiological and psychological capacity to effectively adapt, recover, and maintain optimal functioning in the face of the medical challenges. It encompasses the ability to cope with and overcome adversity, maintain emotional well-being, and promote overall health and healing.

RNA polymerase

From Wikipedia, the free encyclopedia
DNA-directed RNA polymerase
RNA polymerase hetero 27-mer, human
 
RNA polymerase (purple) unwinding the DNA double helix. It uses one strand (darker orange) as a template to create the single-stranded messenger RNA (green).

In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template.

Using the enzyme helicase, RNAP locally opens the double-stranded DNA so that one strand of the exposed nucleotides can be used as a template for the synthesis of RNA, a process called transcription. A transcription factor and its associated transcription mediator complex must be attached to a DNA binding site called a promoter region before RNAP can initiate the DNA unwinding at that position. RNAP not only initiates RNA transcription, it also guides the nucleotides into position, facilitates attachment and elongation, has intrinsic proofreading and replacement capabilities, and termination recognition capability. In eukaryotes, RNAP can build chains as long as 2.4 million nucleotides.

RNAP produces RNA that, functionally, is either for protein coding, i.e. messenger RNA (mRNA); or non-coding (so-called "RNA genes"). Examples of four functional types of RNA genes are:

Transfer RNA (tRNA)
Transfers specific amino acids to growing polypeptide chains at the ribosomal site of protein synthesis during translation;
Ribosomal RNA (rRNA)
Incorporates into ribosomes;
Micro RNA (miRNA)
Regulates gene activity; and, RNA silencing
Catalytic RNA (ribozyme)
Functions as an enzymatically active RNA molecule.

RNA polymerase is essential to life, and is found in all living organisms and many viruses. Depending on the organism, a RNA polymerase can be a protein complex (multi-subunit RNAP) or only consist of one subunit (single-subunit RNAP, ssRNAP), each representing an independent lineage. The former is found in bacteria, archaea, and eukaryotes alike, sharing a similar core structure and mechanism. The latter is found in phages as well as eukaryotic chloroplasts and mitochondria, and is related to modern DNA polymerases. Eukaryotic and archaeal RNAPs have more subunits than bacterial ones do, and are controlled differently.

Bacteria and archaea only have one RNA polymerase. Eukaryotes have multiple types of nuclear RNAP, each responsible for synthesis of a distinct subset of RNA:

  1. RNA polymerase I synthesizes a pre-rRNA 45S (35S in yeast), which matures and will form the major RNA sections of the ribosome.
  2. RNA polymerase II synthesizes precursors of mRNAs and most sRNA and microRNAs.
  3. RNA polymerase III synthesizes tRNAs, rRNA 5S and other small RNAs found in the nucleus and cytosol.
  4. RNA polymerase IV and V found in plants are less understood; they make siRNA. In addition to the ssRNAPs, chloroplasts also encode and use a bacteria-like RNAP.

Structure

T. aquaticus RNA polymerase core (PDB: 1HQM​).
Yeast RNA polymerase II core (PDB: 1WCM​).
Homologous subunits are colored the same:
  orange: α1/RPB3,
  yellow: α2/RPB11,
  wheat: β/RPB2,
  red: β′/RPB1,
  pink: ω/RPB6.

The 2006 Nobel Prize in Chemistry was awarded to Roger D. Kornberg for creating detailed molecular images of RNA polymerase during various stages of the transcription process.

In most prokaryotes, a single RNA polymerase species transcribes all types of RNA. RNA polymerase "core" from E. coli consists of five subunits: two alpha (α) subunits of 36 kDa, a beta (β) subunit of 150 kDa, a beta prime subunit (β′) of 155 kDa, and a small omega (ω) subunit. A sigma (σ) factor binds to the core, forming the holoenzyme. After transcription starts, the factor can unbind and let the core enzyme proceed with its work. The core RNA polymerase complex forms a "crab claw" or "clamp-jaw" structure with an internal channel running along the full length. Eukaryotic and archaeal RNA polymerases have a similar core structure and work in a similar manner, although they have many extra subunits.

All RNAPs contain metal cofactors, in particular zinc and magnesium cations which aid in the transcription process.

Function

An electron-micrograph of DNA strands decorated by hundreds of RNAP molecules too small to be resolved. Each RNAP is transcribing an RNA strand, which can be seen branching off from the DNA. "Begin" indicates the 3′ end of the DNA, where RNAP initiates transcription; "End" indicates the 5′ end, where the longer RNA molecules are completely transcribed.

Control of the process of gene transcription affects patterns of gene expression and, thereby, allows a cell to adapt to a changing environment, perform specialized roles within an organism, and maintain basic metabolic processes necessary for survival. Therefore, it is hardly surprising that the activity of RNAP is long, complex, and highly regulated. In Escherichia coli bacteria, more than 100 transcription factors have been identified, which modify the activity of RNAP.

RNAP can initiate transcription at specific DNA sequences known as promoters. It then produces an RNA chain, which is complementary to the template DNA strand. The process of adding nucleotides to the RNA strand is known as elongation; in eukaryotes, RNAP can build chains as long as 2.4 million nucleotides (the full length of the dystrophin gene). RNAP will preferentially release its RNA transcript at specific DNA sequences encoded at the end of genes, which are known as terminators.

Products of RNAP include:

RNAP accomplishes de novo synthesis. It is able to do this because specific interactions with the initiating nucleotide hold RNAP rigidly in place, facilitating chemical attack on the incoming nucleotide. Such specific interactions explain why RNAP prefers to start transcripts with ATP (followed by GTP, UTP, and then CTP). In contrast to DNA polymerase, RNAP includes helicase activity, therefore no separate enzyme is needed to unwind DNA.

Action

Initiation

RNA polymerase binding in bacteria involves the sigma factor recognizing the core promoter region containing the −35 and −10 elements (located before the beginning of sequence to be transcribed) and also, at some promoters, the α subunit C-terminal domain recognizing promoter upstream elements. There are multiple interchangeable sigma factors, each of which recognizes a distinct set of promoters. For example, in E. coli, σ70 is expressed under normal conditions and recognizes promoters for genes required under normal conditions ("housekeeping genes"), while σ32 recognizes promoters for genes required at high temperatures ("heat-shock genes"). In archaea and eukaryotes, the functions of the bacterial general transcription factor sigma are performed by multiple general transcription factors that work together. The RNA polymerase-promoter closed complex is usually referred to as the "transcription preinitiation complex."

After binding to the DNA, the RNA polymerase switches from a closed complex to an open complex. This change involves the separation of the DNA strands to form an unwound section of DNA of approximately 13 bp, referred to as the "transcription bubble". Supercoiling plays an important part in polymerase activity because of the unwinding and rewinding of DNA. Because regions of DNA in front of RNAP are unwound, there are compensatory positive supercoils. Regions behind RNAP are rewound and negative supercoils are present.

Promoter escape

RNA polymerase then starts to synthesize the initial DNA-RNA heteroduplex, with ribonucleotides base-paired to the template DNA strand according to Watson-Crick base-pairing interactions. As noted above, RNA polymerase makes contacts with the promoter region. However these stabilizing contacts inhibit the enzyme's ability to access DNA further downstream and thus the synthesis of the full-length product. In order to continue RNA synthesis, RNA polymerase must escape the promoter. It must maintain promoter contacts while unwinding more downstream DNA for synthesis, "scrunching" more downstream DNA into the initiation complex. During the promoter escape transition, RNA polymerase is considered a "stressed intermediate." Thermodynamically the stress accumulates from the DNA-unwinding and DNA-compaction activities. Once the DNA-RNA heteroduplex is long enough (~10 bp), RNA polymerase releases its upstream contacts and effectively achieves the promoter escape transition into the elongation phase. The heteroduplex at the active center stabilizes the elongation complex.

However, promoter escape is not the only outcome. RNA polymerase can also relieve the stress by releasing its downstream contacts, arresting transcription. The paused transcribing complex has two options: (1) release the nascent transcript and begin anew at the promoter or (2) reestablish a new 3′-OH on the nascent transcript at the active site via RNA polymerase's catalytic activity and recommence DNA scrunching to achieve promoter escape. Abortive initiation, the unproductive cycling of RNA polymerase before the promoter escape transition, results in short RNA fragments of around 9 bp in a process known as abortive transcription. The extent of abortive initiation depends on the presence of transcription factors and the strength of the promoter contacts.

Elongation

RNA Polymerase II Transcription: the process of transcript elongation facilitated by disassembly of nucleosomes.
RNAP from T. aquaticus pictured during elongation. Portions of the enzyme were made transparent so as to make the path of RNA and DNA more clear. The magnesium ion (yellow) is located at the enzyme active site.

The 17-bp transcriptional complex has an 8-bp DNA-RNA hybrid, that is, 8 base-pairs involve the RNA transcript bound to the DNA template strand. As transcription progresses, ribonucleotides are added to the 3′ end of the RNA transcript and the RNAP complex moves along the DNA. The characteristic elongation rates in prokaryotes and eukaryotes are about 10–100 nts/sec.

Aspartyl (asp) residues in the RNAP will hold on to Mg2+ ions, which will, in turn, coordinate the phosphates of the ribonucleotides. The first Mg2+ will hold on to the α-phosphate of the NTP to be added. This allows the nucleophilic attack of the 3′-OH from the RNA transcript, adding another NTP to the chain. The second Mg2+ will hold on to the pyrophosphate of the NTP. The overall reaction equation is:

(NMP)n + NTP → (NMP)n+1 + PPi

Fidelity

Unlike the proofreading mechanisms of DNA polymerase those of RNAP have only recently been investigated. Proofreading begins with separation of the mis-incorporated nucleotide from the DNA template. This pauses transcription. The polymerase then backtracks by one position and cleaves the dinucleotide that contains the mismatched nucleotide. In the RNA polymerase this occurs at the same active site used for polymerization and is therefore markedly different from the DNA polymerase where proofreading occurs at a distinct nuclease active site.

The overall error rate is around 10−4 to 10−6.

Termination

In bacteria, termination of RNA transcription can be rho-dependent or rho-independent. The former relies on the rho factor, which destabilizes the DNA-RNA heteroduplex and causes RNA release. The latter, also known as intrinsic termination, relies on a palindromic region of DNA. Transcribing the region causes the formation of a "hairpin" structure from the RNA transcription looping and binding upon itself. This hairpin structure is often rich in G-C base-pairs, making it more stable than the DNA-RNA hybrid itself. As a result, the 8 bp DNA-RNA hybrid in the transcription complex shifts to a 4 bp hybrid. These last 4 base pairs are weak A-U base pairs, and the entire RNA transcript will fall off the DNA.

Transcription termination in eukaryotes is less well understood than in bacteria, but involves cleavage of the new transcript followed by template-independent addition of adenines at its new 3′ end, in a process called polyadenylation.

Other organisms

Given that DNA and RNA polymerases both carry out template-dependent nucleotide polymerization, it might be expected that the two types of enzymes would be structurally related. However, x-ray crystallographic studies of both types of enzymes reveal that, other than containing a critical Mg2+ ion at the catalytic site, they are virtually unrelated to each other; indeed template-dependent nucleotide polymerizing enzymes seem to have arisen independently twice during the early evolution of cells. One lineage led to the modern DNA polymerases and reverse transcriptases, as well as to a few single-subunit RNA polymerases (ssRNAP) from phages and organelles. The other multi-subunit RNAP lineage formed all of the modern cellular RNA polymerases.

Bacteria

In bacteria, the same enzyme catalyzes the synthesis of mRNA and non-coding RNA (ncRNA).

RNAP is a large molecule. The core enzyme has five subunits (~ 400 kDa):

β′
The β′ subunit is the largest subunit, and is encoded by the rpoC gene. The β′ subunit contains part of the active center responsible for RNA synthesis and contains some of the determinants for non-sequence-specific interactions with DNA and nascent RNA. It is split into two subunits in Cyanobacteria and chloroplasts.
β
The β subunit is the second-largest subunit, and is encoded by the rpoB gene. The β subunit contains the rest of the active center responsible for RNA synthesis and contains the rest of the determinants for non-sequence-specific interactions with DNA and nascent RNA.
α (αI and αII)
Two copies of the α subunit, being the third-largest subunit, are present in a molecule of RNAP: αI and αII (one and two). Each α subunit contains two domains: αNTD (N-terminal domain) and αCTD (C-terminal domain). αNTD contains determinants for assembly of RNAP. αCTD (C-terminal domain) contains determinants for interaction with promoter DNA, making non-sequence-non-specific interactions at most promoters and sequence-specific interactions at upstream-element-containing promoters, and contains determinants for interactions with regulatory factors.
ω
The ω subunit is the smallest subunit. The ω subunit facilitates assembly of RNAP and stabilizes assembled RNAP.

In order to bind promoters, RNAP core associates with the transcription initiation factor sigma (σ) to form RNA polymerase holoenzyme. Sigma reduces the affinity of RNAP for nonspecific DNA while increasing specificity for promoters, allowing transcription to initiate at correct sites. The complete holoenzyme therefore has 6 subunits: β′βαI and αIIωσ (~450 kDa).

Eukaryotes

Structure of eukaryotic RNA polymerase II (light blue) in complex with α-amanitin (red), a strong poison found in death cap mushrooms that targets this vital enzyme

Eukaryotes have multiple types of nuclear RNAP, each responsible for synthesis of a distinct subset of RNA. All are structurally and mechanistically related to each other and to bacterial RNAP:

  1. RNA polymerase I synthesizes a pre-rRNA 45S (35S in yeast), which matures into 28S, 18S and 5.8S rRNAs, which will form the major RNA sections of the ribosome.
  2. RNA polymerase II synthesizes precursors of mRNAs and most snRNA and microRNAs. This is the most studied type, and, due to the high level of control required over transcription, a range of transcription factors are required for its binding to promoters.
  3. RNA polymerase III synthesizes tRNAs, rRNA 5S and other small RNAs found in the nucleus and cytosol.
  4. RNA polymerase IV synthesizes siRNA in plants.
  5. RNA polymerase V synthesizes RNAs involved in siRNA-directed heterochromatin formation in plants.

Eukaryotic chloroplasts contain a multi-subunit RNAP ("PEP, plastid-encoded polymerase"). Due to its bacterial origin, the organization of PEP resembles that of current bacterial RNA polymerases: It is encoded by the RPOA, RPOB, RPOC1 and RPOC2 genes on the plastome, which as proteins form the core subunits of PEP, respectively named α, β, β′ and β″. Similar to the RNA polymerase in E. coli, PEP requires the presence of sigma (σ) factors for the recognition of its promoters, containing the -10 and -35 motifs. Despite the many commonalities between plant organellar and bacterial RNA polymerases and their structure, PEP additionally requires the association of a number of nuclear encoded proteins, termed PAPs (PEP-associated proteins), which form essential components that are closely associated with the PEP complex in plants. Initially, a group consisting of 10 PAPs was identified through biochemical methods, which was later extended to 12 PAPs.

Chloroplast also contain a second, structurally and mechanistically unrelated, single-subunit RNAP ("nucleus-encoded polymerase, NEP"). Eukaryotic mitochondria use POLRMT (human), a nucleus-encoded single-subunit RNAP. Such phage-like polymerases are referred to as RpoT in plants.

Archaea

Archaea have a single type of RNAP, responsible for the synthesis of all RNA. Archaeal RNAP is structurally and mechanistically similar to bacterial RNAP and eukaryotic nuclear RNAP I-V, and is especially closely structurally and mechanistically related to eukaryotic nuclear RNAP II. The history of the discovery of the archaeal RNA polymerase is quite recent. The first analysis of the RNAP of an archaeon was performed in 1971, when the RNAP from the extreme halophile Halobacterium cutirubrum was isolated and purified. Crystal structures of RNAPs from Sulfolobus solfataricus and Sulfolobus shibatae set the total number of identified archaeal subunits at thirteen.

Archaea has the subunit corresponding to Eukaryotic Rpb1 split into two. There is no homolog to eukaryotic Rpb9 (POLR2I) in the S. shibatae complex, although TFS (TFIIS homolog) has been proposed as one based on similarity. There is an additional subunit dubbed Rpo13; together with Rpo5 it occupies a space filled by an insertion found in bacterial β′ subunits (1,377–1,420 in Taq). An earlier, lower-resolution study on S. solfataricus structure did not find Rpo13 and only assigned the space to Rpo5/Rpb5. Rpo3 is notable in that it's an iron–sulfur protein. RNAP I/III subunit AC40 found in some eukaryotes share similar sequences, but does not bind iron. This domain, in either case, serves a structural function.

Archaeal RNAP subunit previously used an "RpoX" nomenclature where each subunit is assigned a letter in a way unrelated to any other systems. In 2009, a new nomenclature based on Eukaryotic Pol II subunit "Rpb" numbering was proposed.

Viruses

T7 RNA polymerase producing a mRNA (green) from a DNA template. The protein is shown as a purple ribbon (PDB: 1MSW​)

Orthopoxviruses and some other nucleocytoplasmic large DNA viruses synthesize RNA using a virally encoded multi-subunit RNAP. They are most similar to eukaryotic RNAPs, with some subunits minified or removed. Exactly which RNAP they are most similar to is a topic of debate. Most other viruses that synthesize RNA use unrelated mechanics.

Many viruses use a single-subunit DNA-dependent RNAP (ssRNAP) that is structurally and mechanistically related to the single-subunit RNAP of eukaryotic chloroplasts (RpoT) and mitochondria (POLRMT) and, more distantly, to DNA polymerases and reverse transcriptases. Perhaps the most widely studied such single-subunit RNAP is bacteriophage T7 RNA polymerase. ssRNAPs cannot proofread.

B. subtilis prophage SPβ uses YonO, a homolog of the β+β′ subunits of msRNAPs to form a monomeric (both barrels on the same chain) RNAP distinct from the usual "right hand" ssRNAP. It probably diverged very long ago from the canonical five-unit msRNAP, before the time of the last universal common ancestor.

Other viruses use an RNA-dependent RNAP (an RNAP that employs RNA as a template instead of DNA). This occurs in negative strand RNA viruses and dsRNA viruses, both of which exist for a portion of their life cycle as double-stranded RNA. However, some positive strand RNA viruses, such as poliovirus, also contain RNA-dependent RNAP.

History

RNAP was discovered independently by Sam Weiss, Audrey Stevens, and Jerard Hurwitz in 1960. By this time, one half of the 1959 Nobel Prize in Medicine had been awarded to Severo Ochoa for the discovery of what was believed to be RNAP, but instead turned out to be polynucleotide phosphorylase.

Purification

RNA polymerase can be isolated in the following ways:

And also combinations of the above techniques.

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