The word ‘cancer’ came from Latin word ‘cancrum’ meaning crab. It is a group of diseases characterized by uncontrolled cell division leading to the growth of abnormal tissue/ tumor. Cancer is a disease of cell in which abnormal cells containing abnormal genetic content divide without control and invade nearby tissue. Cancer cells transfer through blood and lymph. Oncology, a branch of medicine that deals with etiology, diagnosis, treatment and prevention of cancer. ‘Onco’ is a Greek word meaning tumor.
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Types of Cancer
Carcinoma: Begins in different organs, glands, skin or tissues that cover other organs. E.g. breast cancer, colon cancer, rectal cancer etc.
Sarcoma: Cancer of supportive or connective tissues. Begins in bone, cartilage, muscle or blood vessel. E.g. bone cancer (Osteosarcoma), angiosarcoma, chondrosarcoma, liposarcoma.
Leukemia: Begins in blood forming tissue. E.g. bone marrow cancer.
Lymphoma and myeloma: are cancers of the immune system. Begins in lymphatic system.
Cancer of nervous system: E.g. brain cancer.
Teratoma: Cancer of germ cells (testis or ovary).
Cell Proliferation
Reasons for cell multiplication (proliferation):
- Normal physiologic process
- Response to injury
- Immune responses
- To replace cells that have died
- To replace cells that have been shed as a part of their life cycle (e.g. skin, mucous membrane of GI tract, etc.)
Characteristics of Cancer Cells
- Uncontrolled proliferation
- Abnormal nucleus
- Loss of anchorage - The requirement by normal cells to attach to a surface to grow and divide in vitro; when cells lose anchorage dependence they no longer respond to external growth controls, which often correlates with tumorigenicity in vivo. It is a hallmark of malignant transformation
- loss of contact inhibition- Contact inhibition enables noncancerous cells to cease proliferation and growth when they contact each other. This characteristic is lost when cells undergo malignant transformation, leading to uncontrolled proliferation and solid tumor formation.
- Forms tumor
- Undergoes metastasis & angiogenesis
- Lack of differentiation into specialized cells.
- Increased rate of anaerobic glycolysis
Difference between Normal Cell and Cancer Cell
The main difference between differentiated and undifferentiated cells is that differentiated cells are specialized cells to perform a unique function in the body whereas undifferentiated cells are responsible for replenishing old, injured or dead cells.
Etiology of Cancer
Multi-factorial in origin:
- Physical (e.g. x-ray, gamma ray, UV light etc.)
- Chemical (e.g. asbestos, aflatoxins (Aspergillus flavus and Aspergillus parasiticus), aniline, nitroso compound etc.)
- Biological (viruses like Human Papilloma virus, Hepatitis B virus)
- Environmental factors (physical & chemical agents)
- Genetic
- Mutation
- Life style: tobacco smoking or chewing, alcohol
Mutation
- Sudden change in the chemical structure of the DNA
- The substance which causes mutation is known as ‘mutagen’. (e.g. x-ray, gamma ray)
Carcinogenesis
Cancer initiation and progression process -
- Requires abnormal genetic content
- Requires three steps:
- Activation of proto-oncogene to oncogene
- Deregulation of tumor suppressor gene and DNA repair gene
- Immortalization
Genes Responsible for Cancer
1. Oncogene
Genes which can cause cancer are known as oncogenes. They are present in normal cells as inactive form and are known as proto-oncogenes. We have more than 100 proto-oncogenes on various chromosomes. Example: ras gene, c-myc.
Products of these oncogenes are involved in the regulation of cell cycle. These products may be growth regulating factor/receptor. These oncogenes are under the control of regulator genes and expressed only when required.
2. Tumor suppressor gene
A tumor suppressor gene, are inherent genes that play a role in cell division and DNA repair and are critical for detecting inappropriate growth signals in cells. E.g. p53 protein encoded by TP53 gene, BRCA1, BRCA2 etc. When this gene is mutated, it results in a loss or reduction in its function; in combination with other genetic mutations this could allow the cell to grow abnormally. The loss of function for these genes may lead to cancer. E.g. mutation in codon 47 & codon 72 of TP53 (Arg Pro) may increase the risk of breast and colon cancer 4-5 times.
3. DNA repair gene
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. E.g. XPC, XRCC1, XRCC2 etc. A cell that has accumulated a large amount of DNA damage that can not be repaired, can enter one of three possible states:
- Senescence
- Apoptosis
- Cancer
Immortalization
Normal cells undergo limited number of cell division before entering senescence. But cancerous cells get infinite lifespan.
4. Telomerase reverse transcriptase (TERT)
Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity.
- Telomerase is an enzyme that provides for telomere synthesis and maintenance, thus telomerase may potentially allow for cellular immortality.
- Telomerase activity may promote tumors through multiple, complex mechanisms, especially by subverting the normal DNA synthetic checkpoints.
Molecular Causes of Cancer
1. Abnormal karyotype:
Karyotype can be defined as total morphological characteristics of chromosomes in terms of size, shape & number of chromosomes. If the morphology of the chromosomes are changed, it may lead to cancer. For example, loss of short arm (p) of chromosome 3 & 17 and long arm (q) of chromosome 5 causes lung cancer.
2. Rearrangement of nucleotides:
Rearrangement of nucleotides or base sequence may lead to cancer. Rearrangement of DNA may be of two types:
- Within the same chromosome: homologous rearrangement
- With other chromosome: non-homologous rearrangement
For example: in colorectal cancer, rearrangement of nucleotide occur between chromosome 8 & 16.
3. Mutation:
Change in the sequence of DNA. May occur by either addition, deletion or substitution. These may result in undesirable protein.
Substitution is two types:
- Transition: purine by purine (A by G), pyrimidine by pyrimidine (C by T)
- Transversion: purine by pyrimidine or vice-versa (A by C or C by A etc.)
For example, mutation in BRCA1 & BRCA2 may led to breast cancer.
4. Abnormal genetic content:
Continuous production of protein due to abnormal higher amount of mRNA may cause cancer generation.
5. Activation of oncogene
6. Loss of activity of tumor suppressor gene:
For example, TP53 helps in detecting the defects in DNA of a cell and then decides whether this error can be resolved or would induce apoptosis. Loss of TP53 function may cause colon, breast and prostate cancer.
7. Mutation in DNA repair gene:
For example, mutation in XPC gene may cause lung and colon cancer.
8. Blocking apoptosis:
For example, Bcl2 (B-cell lymphoma 2) apoptosis modifier.
Major Approaches for Cancer Treatment
1. Destruction of neoplastic cells:
i. Chemotherapeutic agents: 5-fluorourocil, methotrexate, cyclophosphamide etc.
ii. Radiation therapy: x-ray, gamma ray
Two way of radiation therapy -
-External beam radiation therapy
-Internal therapy or brachytherapy
m/c: a. directly damage the DNA, b. Produce charged particle or free radicals that damage DNA
iii. Host immunodefence:
- Checkpoint modulators: Nivolumab, pembrolizumab. Immunotherapy drugs called immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.
- Therapeutic antibody: Brentuximab vedotin
2. Surgery:
Colon cancer- Colectomy; breast conserving surgery, laparoscopic surgery, laser surgery, etc.
3. Metastasis blocking:
GPCR and receptor kinase ligands. E.g. Denosumab blocks receptor activator of NF-κB ligands (Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL), thus blocks bone cancer metastasis.
4. Convert tumor cell to normal cell:
In cancer of immature cells of WBC e.g. acute lymphocytic leukemia (ALL), immature WBC cells lack some transcription factors. If these immature cells are exposed to these transcription factors, these immature cells become mature WBC. Still no such drug is available in market.
5. Halt neoplastic cell division:
No cells reproduce forever. Aged cells become senescent. Every time chromosome reproduce, telomere gets shorter. As telomerase dwindle, cell division stopped. P21 acts as molecular switch for telomere induced senescence. P21 helps p53 to perform apoptosis. Modulators of p21 may induce senescence and stop neoplastic cell division.
6. Block angiogenesis:
Bevacizumab blocks VEGF from binding with VEGFR; thus block angiogenesis.
Molecular Mechanism for Resistance against Anticancer Drugs
- Decreased drug uptake: To act as an anticancer drug, the drug must be uptaken by the cancer cells. So, if the cell does not uptake the anticancer drug, the drug will be resistant. E.g. Methotrexate, actinomycin D etc.
- Increased drug efflux: Phosphoglycoprotein (PGP) is over expressed and efflux of drug is increased. The drug then can not act as an anticancer drug. E.g. doxorubicin, actinomycin D etc.
- Decreased conversion to active drug: Some drugs are given as pro-drug. So, these drugs must be activated inside the body. If these drugs are not activated, they will not be able to kill cancer cells. E.g. Cyclophosphamide (inactive) is activated to active cyclophosphamide by metabolic activation.
- Increased conversion of active to inactive metabolite: To kill the cancer cells, the anticancer drug must remain in the active form. But some enzymes may convert the active drug to inactive metabolite. Thus the drug would be resistant. E.g. aldehyde dehydrogenase converts cyclophosphamide to inactive metabolites.
- Rapid repair of DNA damage: Some anticancer drugs kill the cancer cells by damaging the DNA. If the damaged DNA is repaired quickly, the drug will be resistant. E.g. cyclophosphamide, doxorubicin, etc.
- Increased intracellular concentration of the target enzyme: 5-FU inhibits thymidylate synthase. If thymidylate synthase concentration is increased, 5-FU will be resistant.
- Increased expression of apoptosis blocking protein: BCL2 blocks apoptosis. Some drugs that induce apoptosis get resistant due to over expression of BCL2.
- Presence of altered enzyme that is enzymatically active but has lower binding affinity for the drug: Methotrexate binds with DHFR. Altered DHFR does not bind to methotrexate but has normal function.
Targeted Cancer Therapy
Targeted cancer therapy is a form of molecular medicine in which the drug binds with specific molecular target to exert therapeutic activity i.e. to halt neoplastic cell proliferation.
These are mainly two types:
- Small molecules that can enter into the cell e.g. imatinib
- Monoclonal antibody that carry drug to the cell surface e.g. trastuzumab binds to HER-2 (Human Epidermal Growth Factor Receptor-2, inhibit the PI3K/Akt pathway and the MAPK pathway. The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits.).
Available Targeted Therapy
- Hormone therapy: Any drug that is used to block the action of a hormone in a hormone sensitive cancer. e.g. Tamoxifen is used to block the activity of estrogen in ER positive breast cancer.
- Signal transduction inhibitor: Once a cell receives a signal to grow, it is relayed within the cell through a process of biochemical reaction. Imatinib mesylate (tyrosine kinase inhibitor) inhibits the signal transduction of BCR-ABL fusion gene (chronic myeloid leukemia).
- Gene expression modulator: TFO (triplex forming oligonucleotide) are used to repair DNA damage. They are not very useful due to lack of specificity.
- Apoptosis inducer: If any drug can induce apoptosis in mutated cell, then carcinogenesis can be prevented. No such drug is available at the market.
- Angiogenesis inhibitor: New blood vessel production is blocked. E.g. Bevacizumab inhibits VEGF to bind with its receptor, VEGF receptor 2.
Cancer cells are cells that have lost their ability to divide in a controlled fashion. A malignant tumor consists of a population of rapidly dividing and growing cancer cells that progressively accrues mutations. However, tumors need a dedicated blood supply to provide the oxygen and other essential nutrients they require in order to grow beyond a certain size. Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. VEGF) and proteins.
Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect, supply required nutrients, allowing for tumor expansion. Unlike normal blood vessels, tumor blood vessels are dilated with an irregular shape. - Immunotherapy: Drug that trigger host immune system can halt carcinogenesis. Eg: Ipilimumab is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive. Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells.
- Monoclonal antibodies that deliver toxic molecules: Toxic materials attached to monoclonal antibody can specifically bind to and release toxic substance into the cancer cells. For example, ibritumomab tiuxetan can bind to CD20 and destroy cancer cell by releasing radioactive isotope attached to it. The drug uses the monoclonal mouse IgG1 antibody ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90 or indium-111) is added.
