Cancer
Cancer is the abnormal
growth of cells caused by multiple changes in gene expression. These changes cause an imbalance of cell
proliferation and cell death and the cells become able to invade tissues and
metastasize to distant sites. It is a
genetic disease, but in most cases, not an inherited disease.
Cancer is a complex
family of diseases. Carcinogenesis is the events that turn a normal cell in the
body into a cancer cell and is a complex multistep process. Cancer is a disease of abnormal gene
expression which happens by a number of mechanisms. These may be via a direct
insult to DNA, such as a gene mutation, translocation, amplification, deletion,
loss of heterozygosity, or from abnormal gene transcription or translation.
Tumors are of two basic
types: benign and malignant. A tumor that is not capable of indefinite growth
and does not invade the healthy surrounding tissue extensively is benign. A
tumor that continues to grow and becomes progressively invasive is
malignant. Malignant tumors exhibit
metastasis where small clusters of cancerous cells dislodge from a tumor,
invade the blood or lymphatic vessels, and are carried to other tissues, where
they continue to proliferate. In this way a primary tumor at one site can give
rise to a secondary tumor at another site.
The following are
features that differentiate a malignant tumor from a benign tumor:
1
Malignant tumors invade
and destroy adjacent normal tissue. Benign
tumors grow by expansion, are usually encapsulated, and do not invade
surrounding tissue.
2
Malignant tumors
metastasize through lymphatic channels or blood vessels to lymph nodes and
other tissues in the body. Benign tumors remain localized and do not
metastasize.
3
Malignant tumor cells
tend to be anaplastic (less differentiated than normal cells of the tissue in
which they arise). Benign tumors usually resemble normal tissue.
4
Malignant tumors usually
grow more rapidly than benign tumors. Benign tumors often grow slowly over
several years.
The biological properties of cancer cells
The biological properties
of malignant tumor cells are
- Acquisition of self-sufficiency in growth signals, leading to
unchecked growth.
- Loss of sensitivity to anti-growth signals, leading to unchecked
growth.
- Loss of capacity for apoptosis, that allows growth despite genetic
errors and external anti-growth signals.
- The cells are attachment independent and has lost contact
inhibition
- Loss of capacity for senescence, leading to limitless replicative
potential (immortality)
- Acquisition of sustained angiogenesis, allowing the tumor to grow
beyond the limitations of passive nutrient diffusion.
- Acquisition of ability to invade neighboring tissues, becoming
invasive and acquisition of ability to build metastases at distant sites.
Carcinogenesis
Carcinogenesis is a
general term used to denote the development of cancer. A carcinogen is any chemical,
biological agent or radiation that has the ability to damage the genome or to disrupt
cellular metabolic processes leading to cancer.
Development of Cancer Occurs in Stages
Cancers are multistage
diseases progressing through accumulation of multiple genetic changes (lesions)
that influence control of cell proliferation, survival, differentiation,
migration, and social interactions with neighboring cells and stroma. In experimental models, the process has at
least three distinct steps: initiation, promotion, and progression.
Initiation
Initiation can occur
after a single, brief exposure to a carcinogen. Initiationinvolves changes in
the genome.
Promotion
After initiation,
promoters stimulate cell division and lead to malignant transformation. Most promoting agents are mitogens for the
tissue in which promotion occurs. Here the initiated cell clonally expands into
a visible tumor, often a benign lesion such as a papilloma.
Progression
The cells after promotion
undergo one or more additional heritable changes during the progression to a
malignant neoplasm. During this loss of
growth control and an escape from host defense mechanisms become predominant
and progress to a clinically detectable tumor.
Spread of cancer from the
organ of origin (primary site) to distant tissues (metastasis) occurs.
Tumor Metastasis
Tumor metastasis is the
spread of tumor cells from a primary tumor to colonize other sites of the body.
The formation of metastases is a very complex and dynamic process during which
a number of interactions between tumor cells themselves and between tumor cells
and the surrounding environment take place. The steps involved in the process
of metastasis are the "metastatic cascade".
The tumor metastatic
process is a complex cascade of events, including
1) Invasion, often
defined by changes in tumor cell adhesion, proteinase production, and
locomotion,
2) Intravasation, arrest
in, and extravasation from the circulatory system,
3) Colonization,
4) Angiogenesis at a
distant site.
At each step of the
metastatic process tumor cells must avoid immune recognition and lysis.
Metastatic Cascade
Invasion and motility.
Normal tissue requires
proper adhesions with basement membrane and/or neighboring cells to signal to
each other. Tumor cells display diminished cellular adhesion, allowing them to
become motile. Tumor cells use their migratory and invasive properties to burrow
through surrounding extracellular stroma and to gain entry into blood vessels
and lymphatics.
Intravasation and survival in the circulation
Once tumor cells enter
the circulation, or intravasate, they must be able to withstand the physical
shear forces and the hostility of immune cells to travel to distinct sites to
establish the secondary tumor growth. In
the bloodstream, a very small number of tumor cells survive to reach the target
organ. NK cells, macrophages and
lymphocytes contribute to the elimination of tumor cells in the vascular
system. The death of circulating cancer cells may be also caused by very simple
factors like mechanical movement, turbulence and lack of proper nutrition and
metabolism.
Arrest and extravasation.
Once arrested in the
capillary system of distant organs, tumor cells must extravasate, or exit the
circulation, into tissue.
Growth in distant organs.
Successful adaptation of
the extravasated cells to the new microenvironment results in their growth and
development into metastatic tumour.
Pathologically, cancers are classified as:
1. Carcinoma, originating from
epithelial cells in the skin or in tissues that line or cover internal organs,
and typically representing over 80% of diagnosed human cancer each year;
2. Sarcoma, originating in bone,
cartilage, fat, muscle, blood vessels, or other connective or supportive
tissue;
3. Leukemia, a cancer originating in
blood-forming tissues such as the bone marrow, and causing large numbers of
abnormal blood cells to be produced and enter the bloodstream
4. Lymphoma, which originates in the
cells of the immune system.
Cancer involves changes
in two classes of genes – onco genes and tumour suppressor genes
Oncogenes – stimulate
proliferations, inhibit differentiation, inhibit apoptosis
Tumor suppressor genes-
inhibit proliferation, promote differentiation, stimulate apoptosis
Gain-of-function
mutations of proto-oncogenes stimulate cells to multiply.
Loss-of-function
mutations of tumor suppressor genes cause uncontrolled multiplication.
Oncogenes (cancer-causing genes)
Proto-oncogenes are a
family of cellular genes with at least 30 members that appear to be involved in
normal cellular growth and development and play key roles in loss of
differentiation, cell motility and avoidance of apoptosis. Activation
or inappropriate expression of these genes results in proliferative signals
involved in neoplastic growth. In healthy cells, the proto-oncogenes are under
tight regulation to avoid excessive proliferation. Its hyperactivity make it an
oncogenes.
Oncogenes may be divided
into five groups based on the functional and biochemical properties of protein
products of their normal proto-oncogene counterparts. These groups are
(1) Growth factors,
(2) Growth factor receptors,
(3) Signal transducers,
(4) Transcription factors,
(5) Regulators of cell death and others.
Conversion of proto-oncogenes to oncogenes. A proto-oncogene can be converted to an oncogene in a
number of ways.
1.
Point mutations in the
coding region of a single gene (e.g. RAS) that can result in the formation of
an abnormal oncoprotein with enhanced stability or activity
2.
Point mutations in regulatory
elements resulting in enhanced or deregulated expression.
3.
Chromosomal
translocations or rearrangements can lead to over expression of an oncoprotein.
For example, in Burkitt’s
lymphoma, the proto-oncogene c-MYC on chromosome 8 is translocated to one of
the three chromosomes containing the genes that encode antibody molecules:
immunoglobulin heavy chain locus (chromosome 14) or one of the light chain loci
(chromosome 2 or 22). C-MYC now finds itself in a region of vigorous gene
transcription, leading to overproduction of the c-MYC protein.
The BCL-2 Family comprises both proapoptotic and antiapoptotic members, the
balance determines whether or not a cell undergo apoptosis.
Bcl-2 subfamily
(antiapoptotic): Bcl-2, Bcl-XL, Bcl-w, etc.
Bax subfamily
(pro-apoptotic): Bax, Bak and Bok
BH3 subfamily
(pro-apoptotic): Bad, Bid, Bik, etc.
BCL-2 in human follicular
lymphoma involves a chromosome translocation event that moves the BCL-2 gene
from chromosome 18 to 14 linking the BCL-2 gene to an immunoglobulin locus. The
Bcl-2 gene implicated in a number of cancers - melanoma, breast, prostate
and lung carcinomas and involved in resistance to conventional cancer
treatment.
4.
Gene amplification can
lead to overexpression of the oncogene.
5.
Fusion of one protein to
another might lead to its constitutive activity.
Reciprocal translocation
between the ABL chromosome (chromosome 9) and chromosome 22 near a locus termed
the break-point cluster region (BCR). The result is a constitutively active ABL
tyrosine kinase domain fused to the BCR coding region forming the BCR-ABL
fusion protein - the Philadelphia chromosome (Ph+) - chronic myelogenous leukemias (CMLs).
Fusion of the
promyelocytic leukemia (PML) protein to the retinoic acid receptor-alpha (RARα) generates
the transforming protein of acute promyelocytic
leukemias
Tumor suppressors
These are guardians
against DNA damage that may be induced by ultraviolet (UV) exposure from
sunlight, gamma irradiation (X-rays), chemotherapeutic drugs, or an excess of
inappropriate proliferative signals. Tumor suppressor genes prevent cells from
becoming malignant by arresting their proliferation or inducing them to commit
suicide (apoptosis).
Tumor suppressors monitor
critical cellular checkpoints that govern the mitotic cycle, DNA repair,
transcription, apoptosis, and differentiation. The functional inactivation of
tumor suppressors by mutation, deletion, or gene silencing creates an imbalance
between proliferation, cell death, and differentiation programs that
facilitates tumorigenesis.
Example is p53/TP53 “The
guardian of the genome” - a transcription factor - its loss leads to genomic
instability and increased mutagenesis.
BRCA1 and BRCA2 are tumor suppressor genes and are involved
in DNA repair of double-strand breaks. Mutations in either the BRCA1 or BRCA2
genes - high risk for breast and ovarian cancer phenotypes,
Haploinsufficiency is
defined by the appearance of a phenotype in cells or an organism when only one
of the two gene copies or alleles is inactivated. For some tumor suppressor
genes, the loss of a single allele is sufficient to induce susceptibility to
tumor formation and these are haploinsufficient tumor-suppressor genes.
According to Knudson’s
“two hit” hypothesis, loss of
heterozygosity is to be achieved to develop retinoblastoma in the eyes of
children. Here both copies of the gene must be inactivated for cancer to occur.
Carcinogens
Carcinogens are agents
that may damage genes involved in cell proliferation and migration, and may
selectively enhance growth of tumor cells or their precursors. Three classes of
environmental agents – chemical carcinogens (cancer causing chemicals),
ionizing radiation and viruses or other microorganisms (that cause cancer in
animals) have been shown to increase the risk of cancer. They induce mutations that lead to cancer.
The importance of
mutagenesis in the induction of cancer could be exemplifyied by diseases such
as xeroderma pigmentosum. This disorder is caused by a defect in the gene that
encodes a DNA-repair enzyme called UV-specific endonuclease. Individuals with
this disease are unable to repair UV-induced mutations and consequently develop
skin cancers.
Carcinogenic chemicals
Carcinogenic chemicals
such as azo dyes, asbestos, benzene, formaldehyde, and diesel exhaust are
dangerous in high concentrations. Chemical carcinogens taken up by cells are
usually metabolized, and the resulting metabolites are then excreted, but may
on occasion be retained by the cell. Such internalized carcinogenic compounds
can then directly or indirectly alter gene expression. Some carcinogens are
genotoxic, forming DNA adducts or inducing various chromosomal abnormalities.
For example, carcinogenic ions or compounds of nickel, arsenic, and cadmium can
induce aneuploidy. Many carcinogenic compounds are mutagenic – that is, they
can induce mutations in DNA.
Other carcinogens may act
by nongenotoxic mechanisms, including promoting inflammation, suppressing
immunity, forming damaging reactive oxygen species (ROS), or by activation of
signaling pathways and epigenetic silencing.
Some carcinogens are
direct-acting and activation-independent.
Example is alkylating agents. However, the majority are procarcinogens
that require metabolic activation to produce carcinogens. Polycyclic
hydrocarbons (smoke), aromatic amines, amides, azo dyes, and nitrosamines
require activation by the hepatic cytochrome P450 mixed function oxidase
system.
The result of exposure of
a cell to certain carcinogens permanently alters its genetic material but does
not immediately influence phenotype and these are described as mutagens or
genotoxic agents and these are initiators. Promoters are nongenotoxic
carcinogens. The best-known promoters are the phorbol esters.
Ionizing radiation:
Radiation-induced cancers
may represent up to 10% of total cases.
X-rays and nuclear radiation can damage DNA. Radiation-induced cancers
are a stochastic late effect of ionizing or non-ionizing radiation. They include
some leukemia and lymphoma, thyroid cancers, skin cancers, some sarcomas and some
lung and breast carcinomas.
Viruses and other microorganisms:
It is estimated that
oncogenic viruses are involved worldwide in about 16% of neoplasia. Few DNA viruses and diploid RNA viruses
have been shown to be associated with human cancers.
DNA viruses
Cellular transformation
by DNA tumor viruses is due to the result of protein–protein interaction.
Proteins encoded by the DNA tumor viruses, the tumor antigens, or T antigens,
can interact with cellular proteins mainly of the tumorsuppressor type. The
loss of normal suppressor functions results in cellular transformation.
Hepadnaviruses
Hepatitis B virus (HBV) causes hepatocellular carcinoma.
Papillomavirus - Human
papilloma viruses (HPV) cause common warts and cervical carcinoma.
Herpes viruses - Epstein–Barr virus (EBV), the
etiological agent of infectious mononucleosis cause Burkitt’s lymphoma and
nasopharyngeal carcinoma, Hodgkin’s lymphomas. EBV transformation is multigenic
and at least five different viral genes appear to be involved.
Adenoviruses - These
viruses transform cultured cells and cause cancer in animals.
Polyomaviruses - Oncogenic
in laboratory animals and can transform human cells in culture. Polyoma virus and SV40 are linked to a
variety of animal tumors. The latter is known to inactivate both the p53 and RB
tumor suppressors.
Retroviruses
RNA tumor viruses in
humans are Human T-cell leukemia viruses (HTLVs) and the related retrovirus,
human immunodeficiency virus (HIV).
Tumorigenic retroviruses
(oncoviruses) are grouped into three categories based on their mechanism of oncogenicity:
(i) transducing
retroviruses; (ii) cis-activating
retroviruses (iii) trans-activating
retroviruses.
Two features of the
retrovirus life cycle make them acquire and activate oncogenes.
Integration into the cell
chromosome allows the virus to take control of and modify cellular genes. Most retroviruses do not kill the cells they
infect so that genetic alterations are transmitted to daughter cells.
When a retrovirus infects
a cell, its RNA genome is converted into DNA by the viral encoded RNA-dependent
DNA polymerase (reverse transcriptase). The DNA can then integrate stably into
the genome of the host cell. It will be copied
as the host genome is duplicated during normal cell division.
Transducing retroviruses
Integration
in cellular genome may result in rearrangement of the viral genome and
sometimes a portion of the host genome will be incorporated into the viral
genome. This is termed transduction.
Occasionally, transduction results
in the virus acquiring a host gene involved in cellular growth control. The
transduced gene is always altered by either point mutation or deletion. These alterations
serve to activate the transduced gene and result in uncontrolled cellular
proliferation. The transduced genes are termed oncogenes. The expression of the
transduced gene is driven by the virus promoter/enhancer region (LTR). Long
terminal repeats (LTRs) are powerful transcriptional promoter sequences found
at the ends of the retroviral genome. Transducing retroviruses cause tumors at
high efficiency (100% of animals) and with short latency periods (days).
Cis-activating retroviruses
The second mechanism for
retroviral transformation of cells is through the transcription-promoting
action of the LTRs. Retroviral genomes integrate randomly into the host genome,
and may occasionally result in the viral LTRs being placed near to a gene that
encodes a growth regulating protein. This may result in over expression of the
growth-regulatory gene and result in cellular transformation. This is termed
retroviral integration-induced transformation. Tumors formed by these viruses
take longer to occur and not always form tumors.
Example is the induction
of certain cancers by HIV infection.
Trans-acting retroviruses
These viruses may upregulate
cell oncogenes through the action of a viral transactivator protein. The
latency period is long (years) and the efficiency of tumor induction is very
low (1%).
HTLV-1, Human T-cell
leukemia virus is example.
In addition to viruses,
some microflora bacteria of the gastrointestinal tract, including Helicobacter pylori for gastric
neoplasia, some parasites such as Opisthorchis
viverrini for gallbladder cancers, Schistosoma
haematobium for bladder cancer and some oncogenic toxins from moulds
inducing aflatoxins-related HCC are also identified.
Tumor
Antigens
Tumor antigen is an antigenic substance
produced in tumor cells, i.e., it triggers an immune response in the host.
Tumor antigens are useful tumor markers in identifying tumor cells with
diagnostic tests and are potential candidates for use in cancer therapy.
The use of a variety of genetic,
biochemical, and immunological approaches has allowed the identification of
several tumor-associated antigens.
Common tumor antigens offer hope for the design of better therapies, detection,
and monitoring, and have important implications for the possibility of
anti-tumor immunization.
There are 2 main types of
tumor antigens
Tumor-specific transplantation antigens (TSTA) are unique to tumor cells and not expressed on normal cells. They
may result from mutations in tumor cells that generate altered cellular
proteins. Processing of these proteins
gives rise to novel peptides that are presented with class I MHC molecules and
induce a cell-mediated response by tumor-specific CTLs.
They are responsible for rejection of the tumor.
Tumor associated transplantation antigens (TATA) that are expressed by tumor cells and normal cells. They may be
expressed at higher levels on tumor cells when compared to normal cells.
Alternatively, they may be expressed only during development of cells and lost
during adult life but re-expressed in tumors.
These antigens may be proteins that are
expressed on normal cells during fetal development but not expressed in the
adult. They are termed Oncofetal tumor antigens. During embryonic development,
the immune system is immature and unable to respond. Reactivation of the
embryonic genes that encode these proteins results in their expression on tumor
cells. Two well-studied oncofetal
antigens are alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA).
Tumor-associated antigens may also be
proteins that are normally expressed at extremely low levels on normal cells
but are expressed at much higher levels on tumor cells. Examples are growth factors and growth-factor
receptors and oncogene-encoded proteins.
For instance, a variety of tumor cells
express the epidermal growth factor (EGF) receptor at levels 100 times greater
than that in normal cells.
Tumor associated antigens encoded by
cellular oncogenes are also present in normal cells where they are encoded by
the corresponding proto-oncogene. But the levels will be higher on tumor
cells. For example human breast-cancer
cells exhibit elevated expression of the oncogene-encoded Neu protein, a
growthfactor receptor, whereas normal adult cells express only trace amounts of
Neu protein.
Many tumor antigens are cellular proteins
that give rise to peptides presented with MHC molecules. These antigens are able to induce the
proliferation of antigen-specific CTLs or helper T cells. The tumor antigens recognized by human T cells
fall into one of four major categories:
1.
Antigens encoded by genes exclusively
expressed by tumors
2.
Antigens encoded by variant forms of
normal genes that have been altered by mutation
3.
Antigens normally expressed only at certain
stages of differentiation or only by certain differentiation lineages
4.
Antigens that are overexpressed in
particular tumors
Chemically
or physically induced tumor antigens
Even when the same chemical carcinogen induces
two separate tumors at different sites in the same animal, the tumor antigens
are distinct and the immune response to one tumor does not act against the
other tumor. Methylcholanthrene and ultraviolet light are examples.
Tumor
Antigens May Be Induced by Viruses
In contrast to chemically induced tumors,
virally induced tumors express tumor antigens shared by all tumors induced by
the same virus.
Immune
responses to tumors
The immune surveillance theory by Paul
Ehrlich suggested that cancer cells frequently arising in the body are
recognized as foreign and are eliminated by the immune system. Tumors arise
only if cancer cells are able to escape immune surveillance, either by reducing
the tumor antigen expression or due to any impairment in the immune system.
Cytotoxic factors such as TNF-α and TNF-β mediate
tumor-cell killing. The immune response to tumors includes
·
CTL-mediated lysis
·
NK-cell activity
·
Macrophage-mediated tumor destruction
·
Cell destruction mediated by ADCC
NK cells and Macrophages play a significant
role in the immune response to tumors and since they are not MHC restricted and
they express Fc receptors, they can bind to antibody on tumor cells and mediate
ADCC. activated macrophages secrete tumor necrosis factor α.
Tumors may evade the immune response by
modulating their tumor antigens or by reducing their expression of class I MHC
molecules or by antibody mediated or immune complex-mediated inhibition of CTL activity.
Cancer therapy
Conventional cancer treatment
modalities are surgery, chemotherapy and radiation therapy.
Complete removal of the cancer
without damaging the normal tissue of the body is the goal. Sometimes this can
be accomplished by surgery, but this may increase the chance of cancer to
invade adjacent tissue or to spread to distant sites by microscopic metastasis and
chemotherapy and radiotherapy destroy normal cells too. Therefore, cure may be associated with some
level of adverse effects. Cancer therapy
can also include suppressing the cancer to a subclinical state and maintaining it
subsided and palliative care where there is no hope for cure.
Several new methods for
specific and targeted cancer treatment are now being emerging. These are listed below.
Molecular approaches of cancer therapy
Targeted therapies
Immunotherapy
Hormone therapy
Angiogenesis inhibitors
Gene Therapy
Virotherapy
Targeted therapy is currently
a very active research area. Small molecule targeted therapy drugs are
generally inhibitors of enzymatic domains on mutated, overexpressed, or
otherwise critical proteins within the cancer cell. Examples are the tyrosine
kinase inhibitors imatinib and gefitinib
Immunotherapy
Immunotherapy has been used as a novel means of treating cancer. Both active
and passive means of stimulating the non-specific and specific immune systems
have been employed.
Active Immunotherapy
In this, the host actively
participates in mounting an immune response
Specific activation is achieved by using vaccines:
i) Hepatitis
B vaccine
ii) Human
Papilloma virus (HPV) vaccine
Nonspecific activation is achieved by immunization with:
i) Bacillus
Calmette-Guerin (BCG)
ii) Corynebacterium parvum
These activate macrophages to
be tumoricidal.
Passive Immunotherapy
This involves transfer of
preformed antibodies, immune cells and other factors into the hosts.
Specific Passive Immunotherapy
1) Antibodies against tumor
antigens (e.g. Her2/Neu for treatment of breast cancer)
2) Antibodies against IL-2R for
Human T lymphotropic virus (HTLV-1)-induced adult T cell leukemia
3) Antibodies against CD20
expressed on non Hodgkin’s B cell lymphoma.
These antibodies bind to tumor
antigens on the cell surface and activate complement to mediate tumor cell
lysis. In addition cells such as NK cells, macrophages and granulocytes may
bind to the antigen-antibody complexes on the tumor cell surface and mediate
tumor cell killing through antibody-dependent cell-mediated cytotoxicity.
4) Antibodies conjugated to
toxins, radioisotopes and anti-cancer drugs have also been used. These enter
the cells and inhibit protein synthesis. e.g. anti-CD20 conjugated to Pseudomonas
toxin or ricin toxin.
Anti-HER2/neu antibody
trastuzumab (Herceptin) is used in breast cancer, and the anti-CD20 antibody
rituximab is used in a variety of B-cell malignancies
The problems associated with
the use of antibodies
•
Antibodies are not efficient
because the tumor antigens are associated with class I MHC antigens.
•
Tumors may shed antigen or
antigen-antoibody complexes. Thus, immune cells cannot mediate tumor
destruction.
•
Some antibodies may not be
cytotoxic.
•
Antibodies may bind
non-specifically to immune cells expressing the Fc receptors which include NK
cells, B cells, macrophages and granulocytes without binding to tumor cells.
Nonspecific Passive Immunotherapy
i) Adoptive Transfer of lymphocytes: Lymphokine-activated killer (LAK) cells or
Tumor-infiltrating lymphocytes (TIL)
ii) Dendritic cells activated with tumor
antigens may induce tumor-specific T cell responses. As tumor Ags are usually
not known, tumor lysates are used.
iii) Cytokines
§ IL-2: Activates T cells/NK cells expressing IL-2 receptors. This
is used in the treatment of renal cell carcinoma and melanoma
§ IFN-alpha: This induces MHC expression on tumors and used in the
treatment of hairy B cell leukemias
§ IFN-gamma: This increases class II MHC expression; used in the
treatment of ovarian cancers.
§ TNF-alpha: This kills tumor cells.
iv) Cytokine gene transfected tumor cells
may also be used which can activate T or LAK cell-mediated anti-tumor immunity.
Hormone therapy
The growth of some cancers can
be inhibited by providing or blocking certain hormones. Examples of
hormone-sensitive tumors include certain types of breast and prostate cancers.
Removing or blocking estrogen or testosterone is done as treatment.
Angiogenesis inhibitors
Angiogenesis inhibitors
prevent the extensive growth of blood vessels (angiogenesis) that tumors
require to survive. Bevacizumab is an example.
Gene
Therapy
Gene therapy involves an approach that
aims to modify, delete, or replace abnormal gene or genes in a target cancer cell. Several methods have been developed to
facilitate the entry of genetic materials (transgenes) into target cells, using
various vectors.
Once genetic materials are transferred
into target cells and incorporated into nuclear genetic DNA, they may induce
silencing, down-regulation, modification, or repair of the target cell genes.
This may lead to cell death and tumor necrosis (as with the suicide gene), or
impaired cell growth with tumor regression (as with the silencing gene).
Modification of the gene may improve the response from subsequent cancer
therapy, such as chemotherapy, immunotherapy, or radiation.
Suicide genes are transgenes that make up
products that can cause a cell to kill itself through apoptosis.
Gene silencing has been achieved through
delivery of a small interfering double-stranded RNA (siRNA) into target cells,
and subsequent duplex formation of RNA-induced silencing complex (RISC) that
destroys messenger-RNA (mRNA), thus leading to interference with RNA functions
and protein synthesis within the target cells.
Gene modification is helpful in improving
cancer therapy, such as with radiation therapy. Radiosensitizing gene therapy
promotes transgene expression in tumor tissue, thus increasing tumor
sensitivity to radiation.
Gene repair can be achieved using zinc
finger nuclease attached to the lentiviral vector. Once the viral vector enters
the nucleus, it binds to a specific location in the double-stranded DNA,
breaking it at specific location, with subsequent endogenous repair mechanisms,
to create a newly edited double-stranded DNA.
The vectors are broadly divided into two
major categories: viral (or bacterial) and non-viral vectors. Viruses usually bind to target cells and
introduce their genetic materials and transgenes into the host cell as part of
their replication process. For non-viral vectors, different approaches have
been utilized, using physical, chemical, as well as other modes of genetic
transfer such as Electroporation, nanoparticles, liposomes, etc.
Virotherapy - Newcastle disease virus, herpes simplex virus, Adenovirus, Vaccinia virus, etc are under research and clinical trials to be used as oncolytic virus for treatment of tumours
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