Cancer

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Introduction to Cancer

  • Cancer is a disease where cells grow out of control & invade, erode & destroy normal tissue.
  • Normal body cells grow, divide die in an ordinary fasion.
  • cancer cells are different because they do not die, they just continue to grow and divide in a disorderly fashion.
  • The term cancer applies to a group of diseases in which cells grow abnormally. 
  • It may be defined as malignant neoplasm.” 
  • Neoplasm means new growth. 
  • Neoplasia is a general term given to diseases that cause abnormal growth of cells.
  • A mass of tissue formed as a result of abnormal excessive, uncoordinated, autonomous and purpose­less proliferation of cells is called tumor
  • Tumors may be ‘benign’ or “malignant”
  • The term used for all malignant tumors is cancer.

Classification and Nomenclature of Tumors

  • Suffix “oma” is used to denote a neoplasm
  • Benign tumors of surface epithelium is called papilloma e.g.,
    • Squamous papilloma
    • Transitional cell papilloma
    • Columnar cell papilloma
  • Benign tumors of epithelium are called adenoma, e.g. cystadenoma of ovary.
  • Malignant tumors are classified according the tissue and cell types from which they arise e.g.
    • Carcinomas, Cancers of epithelial cells (e.g adenocarcinoma etc.)
    • Sarcomas, cancer of connective tissue and muscles (e.g. osteosarcoma etc.), 
    • Leukemia, these are cancers of stem cells of hemopoietic tissues . They are liquid tumors affecting blood cells mainly WBCs growing in bone marrow
    • Lymphoma, it is a cancer of secondary lymphoid organs like lymph nodes, spleen (e.g. Burkitt’s lymphoma)

Lukemia

Characteristics of Cancer Cells

 Cancer cells are characterized by certain main properties

1. They proliferate rapidly

2. Show diminished growth control

3.  Show loss of contact inhibition. Malignant tumors show faster rate of growth due to loss of contact inhibition and form multilayers instead of a monolayer. 

4. They invade local tissues and spread, or metastasize, to other parts of the body. 

5. They are self-sufficient in growth signals and are insensitive to antigrowth signals

6. They stimulate local angiogenesis 

7.  They are often able to evade (escape) apoptosis 

Molecular basis of CANCER (Carcinogenesis)

  • Carcinogenesis means mechanism of induction of tumors (cancer).
  • Agents which can induce cancer are called carcinogens. 

Carcinogens

  • Agents which can induce cancer are called carcinogens. Carcinogens are a variety of external agents which are divided into three groups:
    • Chemicals 
    • Radiant energy
    • Certain oncogene viruses

Chemical Carcinogens 

  • A wide variety of chemical compounds are carcinogenic 
  • Depending upon the mode of action of carcinogenic chemicals, they are divided into two groups:
    • Initiators of carcinogenesis
    • Promoters of carcinogenesis.

Initiators of Carcinogenesis

  • These are the chemical carcinogens which can initiate the process of abnormal new growth of cells. 
  • Initiation is the first stage in carcinogenesis. 
  • Chemical carcinogens acting as initiators of carcinogenesis can be grouped into two categories
    • Direct carcinogens, 
    • Procarcinogens or Indirect carcinogens

Promoters of carcinogenesis

  • Certain chemical substances are not carcinogenic but they help the initiated cell to proliferate further are called promoters of carcinogenesis. 
  • For example, phenols, phenobarbital, artificial sweetners like saccharine and cyclamates.

Action of chemical carcinogens 

  • Direct or indirect acting carcinogens are usually electrophiles, i.e. they are deficient in electrons (free radicals). 
  • These free radical carcinogens can covalently bind to purines, pyrimidines and phosphodiester bonds of DNA causing un-repairable damage. 
  • These unrepaired damage generate mutations in DNA and mutation in DNA may lead to cancer.

Radiant energy

  • Radiant energy can be carcinogenic.  
  • Ultraviolet rays and ionizing radiation, i.e. X-rays, α-, β-, and γ-rays are mutagenic and carcinogenic. 
  • These rays damage DNA which is the basic mechanism of carcinogenicity with radiant energy. 

These agents can damage DNA by: 

  • Formation of pyrimidine dimers in DNA
  • Formation of apurinic or apyrimidine sites by elimination of corresponding bases
  • Formation of single or double strands breaks or cross linking of DNA
  • Additionally, X-rays and γ-rays can induce formation of reactive oxygen species (ROS), free radicals. Formation of highly reactive free radicals can interact with DNA and other macromolecules leading to molecular damage. 
  • Damage to the DNA results in mutagenesis and thereby probably contributes to carcinogenic effects of radiant energy.

Oncogenic viruses

  • Both DNA and RNA viruses have been identified as being able to cause cancer in humans.
  • The RNA viruses use RNA as the genome. RNA oncogenic viruses are retroviruses, i.e. they contain the enzyme reverse transcriptase
  • All retroviruses are not oncogenic. 

Mechanism of Viral Oncogenesis

  • The genetic material of viruses is incorporated into the genome of the host cell. 
  • The DNA virus infects the host cell. Then DNA virus binds tightly to host cell DNA and causes alterations in gene expression and thus causes cell transformation by altering the types of protein made in cell. 
  • Viral oncoproteins bind to tumor suppressors and inactivate them. 
  • DNA viruses act by down regulating the function of tumor suppressor genes P53 and RB and their protein products.
  • The RNA viruses use RNA as the genome. 
  • The RNA gets copied by reverse transcriptase to produce single strand of viral DNA. 
  • Single strand of viral DNA is then copied to form another strand of complementary DNA, resulting in double stranded viral DNA called the provirus
  • The provirus is then integrated into the DNA of the host cell DNA and results in various activities such as:
  • Deregulation of the cell cycle
  • Inhibition of apoptosis
  • Abnormalities of cell signalling pathways

Oncogenes and proto-oncogenes

  • An oncogene is an altered gene derived by “activation” of normal cellular proto-oncogenes. 
  • Oncogenes encode a wide variety of proteins that accelerate cell growth or cell division. 
  • Cellular proto-oncogenes code for a number of proteins, e.g. growth factors, receptors, transcription factors and other proteins involved in cell growth.  
  • When proto-oncogenes get mutated they become oncogenes
  • Proto-oncogenes are activated to oncogenes by various mechanisms:
    • Promoter and enhancer insertion
    • Gene amplification
    • Chromosomal translocation
    • Point mutation

Activation of Proto-oncogenes to Oncogenes

  •  Activation of proto-oncogenes to oncogenes may be brought about by several mechanisms

1. Insertion of a promoter

  • When viral genome is incorporated into host cell genome, a viral promoter may be placed just upstream of a proto-oncogene
  • This can cause excessive expression of the proto-oncogene resulting in an abnormally high rate of cell growth

2. Insertion of an enhancer

  •  Incorporation of viral genome into host cell genome may place a proto-oncogene under the control of a viral enhancer element
  •  The enhancer element will cause increased expression of the normal proto-oncogene

3. Gene amplification

  • Multiple copies of a gene may be formed in the genome by gene amplification
  • Amplification of some genes is seen in certain Cancers
  • If a proto-oncogene is amplified, its product will be formed in large quantities leading to excessive cell growth.

4. Chromosomal translocation

  • In some cancer cells, abnormal chromosomes are seen which result from translocation of a fragment of chromosome from one chromosome to another
  • Sometimes, the translocation is reciprocal e.g. in Burkitt’s lymphoma
  • In Burkitt’s lymphoma, reciprocal translocation occurs between chromosomes 8 and 14 as a result of which the myc gene of chromosome 8 migrates to chromosome 14, and is placed under the control of enhancer element of heavy (H) chain immunoglobulin gene
  • Therefore, the expression of myc gene is increased

Point mutation

  • A single base substitution in a proto-oncogene may lead to the synthesis of an abnormal protein
  • A gene implicated in several cancers is the ras proto-oncogene
  • It encodes a protein, p 21 which is a component of a long signal transduction pathway involving EGF and perhaps some other growth factors and hormones
  • Thus, activated proto-oncogenes can transform a healthy cell into a cancer cell either due to:
    • Over-expression of genes resulting in excessive formation of the normal gene products
    • Formation of abnormal gene products
  • Oncoviruses transform infected cells by inserting their oncogene(s) into the DNA of the infected cells
  • This leads to excessive growth of the host cell
  • The oncogenes are mutated versions of protooncogenes
  • The mutant oncogenes are not subject to normal regulation and their protein products are abnormal
  • To differentiate between the proto-oncogenes normally present in animal cells and the closely similar oncogenes present in viruses, letter ‘c’ is put before the names of cellular proto-oncogenes and ‘v’ before the names of viral oncogenes
  •  Thus c-ras means the ras proto-oncogene present in animal cells, and v-ras means the ras oncogene present in viruses
  • When oncogenes are expressed, they produce mutated versions of:
    • Growth factors
    • Receptors for growth factors
    • Proteins involved in signaling gene expression in the nucleus.

TUMOR SUPPRESSOR GENES 

  • tumor suppressor gene produces a protein product that normally suppresses cell growth or cell division. 
  • It regulates cell cycle and apoptosis
  • These tumor suppressor genes, sometimes called recessive oncogenes or anti-oncogenes. 
  • When such a gene is altered by mutation, the inhibitory effect of its product is lost or diminished, leading to increased cell growth or cell division. 
  • Inactivation by mutation of tumor suppressor gene removes certain mechanisms of growth control and can cause some types of tumor. 
  • Two of the most widely studied tumor suppressor genes are retinoblastoma (RB) gene and P53gene.

APOPTOSIS

  • Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die, activate enzymes capable of degrading the cells’ own nuclear DNA and nuclear and cytoplasmic proteins. 
  • Fragments of the apoptotic cells then break off; giving the appearance that is responsible for the name (apoptosis, Greek dropping off” or falling off)
  • The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that the cell and its fragments become targets for phagocytes. 
  • The dead cell is rapidly cleared before its contents have leaked out, and therefore cell death by this pathway does not produce an inflammatory reaction in the host. 
  • Thus, apoptosis differs from necrosis, which is characterized by loss of membrane integrity, enzymatic digestion of cells, leakage of cellular contents, and frequently a host reaction.
  • Causes of Apoptosis  
  • Apoptosis in Physiologic Situations  
  • Apoptosis in Pathologic Conditions  
  • Mechanisms of Apoptosis  
  • Clearance of Apoptotic Cells
  • Examples of Apoptosis

Tumor biomarkers 

  • Many cancers are associated with abnormal production of enzymes, proteins, and hormones that can be measured in plasma or serum. 
  • These molecules are known as tumor biomarkers, which may suggest the presence of a type of cancer.. 

Clinical applications of tumor biomarkers

Tumor biomarkers can be used in a number of ways including:

  • Screening in general population
  • Differential diagnosis in symptomatic individuals
  • Clinical staging of cancer
  • Prognosis of disease 
  • Evaluation of success of treatment
  • Detection of recurrence of cancer
  • Monitoring of response to therapy

BIOCHEMICAL BASIS OF CANCER THERAPY

  • Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy and targeted therapy (including immunotherapy). 
  • 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. 
  • Surgery and radiation therapy are the principal methods of treating the primary tumor

Biochemical Basis Of Chemotherapy

  • Cytotoxic chemotherapy has been the main mode of drug treatment of cancer. 
  • Chemotherapeutic drugs are not cancer specific. These drugs not only act against specific cancer cells, but also act on the normal cells, such as bone marrow, skin and GI tract mucosa. 
  • This action on normal cells produces undesired side effects. It kills cells by promoting apoptosis and sometimes necrosis. 
  • Different cytotoxic drugs work at different stages in the cell cycle. 
  • Chemotherapeutic drugs are classified according to their mode of action.
    • DNA damaging drugs
    • Antimetabolites
    • DNA repair inhibitor
    • Antitubilin agents

Biochemical Basis Of Radiotherapy

  • Radiation delivers energy to tissues, causing ionization and excitation of atoms and molecules. 
  • The biological effect is extended thorough the generation of single- and double- strand DNA breaks. 
  • This in turn induces apoptosis of cells through the production of short lived free radicals (oxygen derived free radicals) which damage proteins and membranes.  

Biochemical Basis Of 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
  • Estrogen is capable of stimulating the growth of breast and endometrial cancers 
  • Androgen the growth of prostate cancer. 

Biochemical Basis Of Targeted drug therapy

  • Cancer cells have changes in their genes (DNA) that make them different from normal cells. 
  • Targeted drugs target those differences that help a cancer to grow. 
  • There are many different targets on cancer cells and different drugs that target them. 
  • Some targeted drugs called biological therapies
  • Targeted drugs might:
    • Stop cancer cells from dividing and growing
    • Seek out cancer cells and kill them
    • Encourage the immune system to attack cancer cells
    • Stop cancers from growing blood vessels
    • Help carry other treatments such as chemotherapy, directly to the cancer cells

Types of targeted drugs

  • There are many different types of targeted drugs that can be grouped according to the effect they have. For example, 
    • Cancer growth blockers stop the proteins that trigger the cancer cell to divide and grow. 
    • Anti-angiogenic drugs : Drugs that block cancer blood vessel growth. They stop cancers from growing blood vessels. 
    • Other groups include a particular type of drug, such as a monoclonal antibody. Target specific proteins on cancer cells.  

Biochemical Basis Of Immunotherapy

  • Immunotherapy uses our immune system to fight cancer. It works by helping the immune system recognize and attack cancer cells. 
  • Some types of immunotherapy are also called targeted treatments or biological therapies.  
  • There are different types of immunotherapy

Monoclonal antibodies (MABs)

  • MABs trigger the immune system by attaching themselves to proteins on cancer cells. 
  • This makes it easier for the cells of the immune system to find and attack the cancer cells. 
  • This process is called antibody dependent cell mediated cytotoxicity (ADCC).

Cytokines 

  • Cytokines are a group of proteins in the body that play an important part in enhancing the immune system. 
  • Interferon and interleukin are types of cytokines found in the body. 
  • Scientists have developed man made (recombinant proteins) versions of these to treat some types of cancer.

Other Biochemistry Notes :-

Biochemistry of Proteins

Carbohydrate Metabolism

VITAMIN PYRIDOXINE AND BIOTIN

Vitamin A

VITAMIN D

Pyrimidine metabolism

Purine Metabolism

Cardiac Biomarkers

. Blood Metabolism (Heme synthesis and breakdown)

Haemoglobinopathies

DNA Repair

Regulation of gene expression

DNA Replication

Transcription

Protein synthesis and genetic code

Detoxification (Xenobiotics)

Liver Function Test

Transamination Deamination & Urea Cycle

METABOLISM OF INDIVIDUAL AMINO ACIDS

Hydroxy amino acids

ACIDIC AMINO ACIDS (Aspartate and Glutamate)

Inborn Error Of Phenyl alanine, Tyrosine Metabolism

Electron Transport Chain & Biological Oxidation

RENAL FUNCTION TEST

Biochemistry Of Sodium, Potassium & Chloride

Congenital Kidney Diseases

Glucose Estimation

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