Cancer (Concept of oncogenes and tumor suppressor genes with special referencetop53, Retinoblastoma and Ras and APC) Cancer is a non-infectious disease. It starts at the molecular level of the cell and, ultimately affects the cellular behavior. It can be defined as uncontrolled proliferation of cells without any differentiation. Cancer is a genetic disease because it can be traced to alterations within specific genes. Most cancer cells experience a breakdown in all of these regulatory influences that protect the body from chaos and self‐destruction. Cancer cells proliferate uncontrollably, producing Malignant tumors that invade surrounding healthy tissue. Malignant tumors tend to metastasize, that is, to spawn renegade cells that break away from the parent mass, enter the lymphatic or vascular circulation, and spread to distant sites in the body where they establish lethal secondary tumors that are no longer amenable to surgical removal. All types of cancer can result from uncontrolled Cell Growth And Division of any of the different kinds of cells in the body. The uncontrolled cell growth produces a mass of cells which are called tumors or neoplasm tumors may be Benign or Malignant. Oncogenes encode proteins that promote the loss of growth control and the conversion of a cell to a malignant state and Cell Proliferation. Oncogenes may lead to genetic instability, prevent a cell from becoming a victim of apoptosis, or promote metastasis. Tumor‐suppressor genes act as a cell’s brakes; they encode proteins that restrain cell growth and prevent cells from becoming malignant. The first tumor suppressor gene to be studied and eventually cloned is associated with a rare childhood cancer of the retina of the eye, called Retinoblastoma. The gene responsible for this disorder is named RB . RAS refers to a family of genes that encode proteins involved in cell signaling pathways regulating cell growth and differentiation. APC stands for Adenomatous Polyposis Coli. It's a tumor suppressor gene that plays a critical role in regulating cell proliferation and maintaining the integrity of the epithelial lining of the colon and rectum. Mutations in the APC gene are associated with familial adenomatous polyposis (FAP), an inherited condition characterized by the development of numerous polyps in the colon and rectum, leading to a significantly increased risk of colorectal cancer. The cells of patients with this condition were found to contain a deletion of a small portion of chromosome 5, which was subsequently identified as the site of a tumor‐suppressor gene called Adenomatous Polyposis Coli, or APC . APC is known to suppress the Wnt pathway, which activates the transcription of genes, that promote cell proliferation. Loss of APC function could therefore lead directly to abnormal chromosome segregation and aneuploidy.

1. SUBMITTED TO :
DR. SANTOSH SINGH
ASSISTANT PROFESSOR
CANCER
PRESENTATION BY :
RUBIN SAHU
23062132
M.SC. ZOOLOGY
1ST SEMESTER

2. Introduction
 Cancer is a non-infectious disease. It starts at the molecular level of
the cell and, ultimately affects the cellular behavior.
 It can be defined as uncontrolled proliferation of cells without any
differentiation.
 Cancer is a genetic disease because it can be traced to alterations
within specific genes.
 Most cancer cells experience a breakdown in all of these regulatory
influences that protect the body from chaos and self‐destruction.
 Cancer cells proliferate uncontrollably, producing Malignant tumors
that invade surrounding healthy tissue.
 Malignant tumors tend to metastasize, that is, to spawn renegade
cells that break away from the parent mass, enter the lymphatic or
vascular circulation, and spread to distant sites in the body where
they establish lethal secondary tumors that are no longer amenable
to surgical removal.
Normal Tissue Proliferation
Cancerous Tissue Proliferation

3. Difference Between Normal and Cancerous
Cells

4. Types Of Tumors
 All types of cancer can result from uncontrolled Cell Growth And Division of any of the
different kinds of cells in the body.
 The uncontrolled cell growth produces a mass of cells which are called tumors or
neoplasm tumors may be Benign or Malignant.

5. Types of Cancer
On The Basis
of Cell Types
Lymphoma Leukemia Carcinoma Sarcoma
On the basis of
Tissues of
Origin
Fibro-Sarcoma
Erythroid
Leukemia

6. On the Basis of Cell Types
Lymphoma : There is excessive production of lymphocytes by the
lymph nodes and spleen.
Leukemia : Leukemia are commonly known as blood cancer.
Leukemia’s are neoplastic growth (uncontrolled cell
growth at the cost of remaining cells) of leucocytes or
WBC.
Carcinoma : Carcinomas are principally derived from epithelial cells
of ectoderm and endoderm. The solid tumors in nerve
tissue and in tissues of body surfaces or their attached
glands are example of carcinomas. Cervical, breast, skin
and brain carcinomas are developed from malignant
tumor.
Sarcoma : Sarcomas are solid tumors of connective tissues such
as muscle, bone, cartilage and fibrous tissue.

7. On the basis of Tissues of Origin
Fibro- : A fibrosarcoma is a malignant (cancerous) tumor
that originates in the connective fibrous tissue
found at the ends of bones of the arm or legs, and
then spreads to other surrounding soft tissues.
Erythroid
Leukemia
: Erythroid leukemia is a cancer of the blood and
bone marrow. Erythroleukemia is different from
other subtypes of AML (Acute Myeloid Leukemia)
because it mostly involves a type of blood-
forming cell called the erythroblasts.
Erythroleukemia occurs when your body produces
a large amount of abnormal red blood cells in the
blood and bone marrow. Erythroid Leukemia
Fibro Sarcoma

8. Development of Cancer

9. Properties of Cancer Cells
 Immortalization: Transformed cell cultures can go
on indefinitely and remain immortal if the nutrition is
provided and overcrowding avoided.
 Loss of Contact Inhibition: Cancer cells continue to
multiply and pile up forming irregular masses several
layers deep. In the cell coat fibronectin, a large
glycoprotein found in moving cultured cells is
reduced in cancerous cells.
 Invasiveness: Malignant cells generally secrete
proteases that digest extracellular matrix
components, allowing the cancer cells to invade
adjacent normal tissues.
 Angiogenesis: Cancer cells also secrete growth factors that promote the formation of new blood
vessels.
 Failure to Differentiate: Another general characteristic of most of the cancer cells is that they fail to
differentiate.
 Auto stimulation of Cell Division: Cancer cells produce growth factor that stimulates their own cell
division. Such abnormal production of a growth factor by the cancer cell leads to continuous auto
stimulation of cell division.

10. Genes Involved in Cancer
 There exist 2 classes of such cancer genes:
 The Oncogenes: Function as Positive Growth Regulators.
 The Tumor Suppressor Genes: Function as Negative Growth Regulators.
Cancer Genes
Oncogenes
Tumor
Suppressor
Genes

11. Oncogenes
 Oncogenes encode proteins that promote the loss of growth control
and the conversion of a cell to a malignant state and Cell
Proliferation.
 Oncogenes may lead to genetic instability, prevent a cell from
becoming a victim of apoptosis, or promote metastasis.
 The existence of oncogenes was discovered through a series of
investigations on RNA tumor viruses that is documented in the
Experimental Pathways.
 These viruses transform a normal cell into a malignant cell because
they carry an oncogene that encodes a protein that interferes with
the cell’s normal activities.
 It was discovered that an oncogene called src, carried by an RNA
tumor virus called avian sarcoma virus, present in the genome of
uninfected cells.
 The oncogene was not a viral gene, but a cellular gene that had
become incorporated into the viral genome during a previous
infection. It soon became evident that cells possess a variety of
genes, now referred to as Proto‐oncogenes, that have the potential
to subvert the cell’s own activities and push the cell toward the
malignant state.

12. Oncogenes
Proto‐oncogenes encode proteins that have various
functions in a cell’s normal activities. Oncogenes acts
dominantly. Proto‐oncogenes can be converted into
oncogenes (i.e., activated) by several mechanisms:
 The gene can be mutated in a way that alters
the properties of the gene product so that it no
longer functions normally.
 The gene can become duplicated one or more
times, resulting in gene amplification and
excess production of the encoded protein.
 A chromosome rearrangement can occur, which
can either alter the expression of the gene or
the nature of the gene product.
Mechanism of Activation of Proto-Oncogenes to Oncogenes

13. Tumor Suppressor Genes : p53
 Tumor‐suppressor genes act as a cell’s brakes; they
encode proteins that restrain cell growth and prevent
cells from becoming malignant.
 In many tumors these genes are lost or inactivated,
thereby removing negative regulators of cell
proliferation and contributing to the abnormal
proliferation of tumor cells. Normally, the function of
tumor suppressor gene is just opposite to oncogene.
 The TP53 gene may have more to do with the
development of human cancer than any other
component of the genome.
 TP53 is the most commonly mutated gene in human
cancers; approximately half of all human tumors contain
cells with point mutations or deletions in both alleles of
the TP53 gene.

14.  The frequency with which both alleles of the TP53
gene are mutated in different types of cancers.
 p53 function is particularly sensitive to mutations in
DNA‐binding domain.
 p53 functions as a tetramer, each subunit of which
consists of several domains with different functions.
 The six amino acid residues most often mutated in
p53 molecules that have been debilitated in human
cancers are indicated in a single‐letter nomenclature
 These residues occur at or near the protein–DNA
interface and either directly impact the binding of the
protein to DNA or alter its conformation.
Role of Tumor Suppressor Genes : p53 in
Human Cancer

15. A model for the function of p53
 Cell division does not normally require the involvement of p53.
 However, the DNA of a cell becomes damaged as the result of exposure to mutagens, the level
of p53 rises and acts either to arrest the progression of the cell through G1 or to direct the cell
toward apoptosis.
 If both copies of the TP53 gene are inactivated, the cell loses the ability to arrest the cell cycle
or commit the cell to apoptosis following DNA damage.
 As a result, the cell either dies from mitotic failure or continues to proliferate with genetic
abnormalities that may lead to the formation of a malignant growth.

16. Retinoblastoma
 The first tumor suppressor gene to be studied and eventually
cloned is associated with a rare childhood cancer of the retina of
the eye, called Retinoblastoma.
 The gene responsible for this disorder is named RB .
 The incidence of retinoblastoma follows two distinct patterns:
 (1) It occurs at high frequency and at young age in members of
certain families
 (2) it occurs sporadically at an older age among members of the
population at large.
 One member of the 13th pair of homologous chromosomes
was missing a small piece from the interior portion of the
chromosome, leading to the Retinoblastoma.
 Retinoblastoma is inherited as a dominant genetic trait.

17. Mechanism of pRB gene Activation
 The protein encoded by the RB gene, pRB, helps regulate the passage of
cells from the G1 stage of the cell cycle into S phase, during which DNA
synthesis occurs.
 The pRB protein binds to and inhibits certain transcription factors known as
E2F transcription factors, which plays a crucial role in activating genes
required for DNA replication and cell proliferation.
 When the pRB protein binds to E2F, it prevents E2F from activating these
genes, thereby halting cell cycle progression.
 This inhibition of E2F activity by the RB protein helps control cell growth and
prevent uncontrolled proliferation.
 Various Cell Signaling pathways, induces phosphorylation of pRB protein,
which leads to the dissociation of pRB-E2F complex, thereby activating
genes for cell cycle for growth and proliferation.
 Mutation in these genes can induce the uncontrolled growth and
proliferation of the tumor.
 The risk of developing retinoblastoma is increased because only one
additional mutation is required to inactivate both copies of the RB gene in a
retinal cell, leading to tumor formation.

18. RAS (Rat Sarcoma Gene)
 RAS refers to a family of genes that encode proteins involved in cell
signaling pathways regulating cell growth and differentiation.
 These proteins are members of the larger Ras superfamily of GTPases,
which act as molecular switches, toggling between active (GTP-bound)
and inactive (GDP-bound) states to transmit signals from cell surface
receptors to the cell's interior.
 The three main members of the RAS gene family are HRAS, KRAS, and
NRAS encoding for proteins known as Ras proteins (H-Ras, K-Ras, and
N-Ras, respectively), which are crucial components of intracellular
signaling networks.

19. Mutation in RAS
 Activation by Guanine Nucleotide Exchange Factors (GEFs): In their inactive state, RAS proteins
are bound to GDP (guanosine diphosphate). To become active, RAS proteins must exchange GDP for
GTP, a process facilitated by Guanine Nucleotide Exchange Factors (GEFs).
 Signal Transduction: Once activated by GTP binding, RAS proteins serve as molecular switches that
relay extracellular signals from cell surface receptors, such as receptor tyrosine kinases (RTKs), to
intracellular signaling pathways.
 Hydrolysis of GTP to GDP: The GTPase activity of RAS proteins allows them to switch off signaling by
hydrolyzing GTP to GDP. This hydrolysis process is intrinsic to RAS proteins but can be enhanced by
GTPase Activating Proteins (GAPs), which accelerate the hydrolysis of GTP.
 Inactivation and Regulation: In addition to GAPs, RAS signaling is regulated by Guanine Nucleotide
Dissociation Inhibitors (GDIs), which sequester inactive RAS in the cytoplasm, preventing its
reactivation.
 Mutations in RAS genes, particularly in the GTP-binding domain, can impair the GTPase activity of RAS
proteins, leading to prolonged signaling and dysregulated cell growth, which can contribute to cancer
development.

20. Adenomatous Polyposis Coli Gene
(APC Gene)
 APC stands for Adenomatous Polyposis Coli.
 It's a tumor suppressor gene that plays a critical role in regulating cell
proliferation and maintaining the integrity of the epithelial lining of the
colon and rectum.
 Mutations in the APC gene are associated with familial adenomatous
polyposis (FAP), an inherited condition characterized by the
development of numerous polyps in the colon and rectum, leading to a
significantly increased risk of colorectal cancer.
 The cells of patients with this condition were found to contain a
deletion of a small portion of chromosome 5, which was
subsequently identified as the site of a tumor‐suppressor gene called
Adenomatous Polyposis Coli, or APC .
 APC is known to suppress the Wnt pathway, which activates the
transcription of genes, that promote cell proliferation.
 Loss of APC function could therefore lead directly to abnormal
chromosome segregation and aneuploidy.

21. Mechanism of APC
 APC serves as a tumor suppressor by regulating the
Wnt signaling pathway, crucial for controlling cell
proliferation and differentiation.
 It forms a destruction complex with other proteins
to regulate the levels of β-catenin, a key component
of Wnt signaling.
 APC facilitates the degradation of β-catenin,
preventing its accumulation and translocation into
the nucleus to activate Wnt target genes involved in
cell proliferation and survival.
 Additionally, APC is involved in regulating cell
adhesion, migration, and cytoskeletal organization,
contributing to tissue architecture.
 Mutations in the APC gene disrupt its function,
leading to dysregulated Wnt signaling, uncontrolled
cell proliferation, and the development of colorectal
cancer, as seen in familial adenomatous polyposis
(FAP) and sporadic cases.