Cancer cell

1. Course no.: 503
Course title : Molecular cell biology
Submitted to :
Dr. Shraddha B. Bhatt
Assistant professor
Department of Biotechnology
JAU , Junagadh.
Submitted by :
Badal Kangad
Reg.no. : 2010123002
MSc.(Agri)

2.  HALLMARKS OF CANCER…

3. 1) Uncontrolled growth of cells of a tissue in higher organisms.
2) Two classes of genes are critical in the causation of cancer - tumor
suppressor genes (p53 gene) and proto oncogenes.
3) Loss of function due to mutations of tumor suppressor genes and
gain of function due to mutations of proto oncogenes leads the
normal cells to cancerous cells.
4) p53 is a cancer suppressor gene and acts as a guardian of cellular
DNA .
5)The protein coded by p53 gene helps DNA repair and suppresses
the cancer.
Cancer :

4. CANCER AND ITS TYPES :
 Benign tumors not cancerous. They can often be removed, and in most cases, they do not
come back. Cells in benign tumors don not spread to other parts of the body.
 Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and
spread to other parts of the body. The spread of cancer from one part of the body to
another is called metastasis.
Cancer types can be grouped into broader categories. The main categories of cancer
include:
Carcinoma - cancer that begins in the skin or in tissues that line or cover internal organs.
Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels or other
connective or supportive tissue.
Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes
large numbers of abnormal blood cells to be produced and enter the blood stream.
Lymphoma and Myeloma - cancer that begin in the cells of the immune system.
Central nervous system cancers - cancer that begin in the tissues of the brain and spinal
cord.

5.  Normal Cell To Cancer developments :

6.  HALLMARKS OF CANCER
 Biologic capabilities acquired by
cancer cells during the multistep
process of development of human
tumors.
 Essential Alterations In Cell
Physiology That Collectively Lead To
Malignant Growth Of A Normal
Cells.
 Described by Douglas Hanahan &
Robert Weinberg in 2000.

7. SIX FUNDAMENTAL CHANGES
1. Self sufficiency in growth factors.
2. Insensitivity to growth-inhibitory signals.
3. Evasion of apoptosis.
4. Limitless replicative potential.
5. Sustained angiogenesis.
6. Ability to invade and metastasize.
 With development in genetics and epigenetics Hanahan and Weinberg again
redefined "Hallmarks of cancer" in 2011.
 Two additional hallmarks of cancer are:
7. Evading immune destruction.
8. Deregulating cellular metabolism or energetics.

8. ACCORDING TO Douglas Hanahan & Robert Weinberg
IN 2000, SIX HALLMARKS OF CANCER

9. 1. SELF-SUFFICIENCY IN GROWTH
SIGNALS…
 Cancer cells do not need stimulation from external signals (in the form of
growth factors) to multiply.
 Normal cells require external growth signals (growth factors) to grow and
divide. These signals are transmitted through receptors that pass through
the cell membrane. When the growth signals are absent, they stop growing.
Cancer cells can grow and divide without external growth signals.
 Cancer cells can generate their own growth signals. For example,
glioblastomas can produce their own platelet-derived growth factor(PDGF),
and sarcomas can produce their own tumor growth factor-α(TGF-α).
 Receptors themselves can be over expressed. For example, the epidermal
growth factor receptor (EGF-R/erb-B) is over expressed in stomach, brain and
breast cancers, while the HER2/neu receptor is overexpressed in stomach
and breast cancer. Or, mutated receptors can send signals without any
growth factors at all.

10. 2. INSENSITIVITY TO ANTI-GROWTH
SIGNALS...
 Cancer cells are generally resistant to growth-preventing
signals from their neighbours.
 The growth of normal cells is kept under control by growth
inhibitors in the surrounding environment, in the
extracellular matrix and on the surfaces of neighboring cells.
These inhibitors act on the cell cycle clock, by interrupting
cell division (mitosis) in the interphase.
 Ultimately, the growth inhibitor signals are funneled through
the downstream retinoblastoma protein (pRB), which
prevents the inappropriate transition from (G ) to S. If pRB is
₁
damaged through a mutation in its gene, or by interference
from human papilloma virus, the cell can divide
uncontrollably, which can lead to cervical cancer.

11. 3. EVADING APOPTOSIS…
 Normally when cells become old or damaged they are programmed
to die in a process called apoptosis.
 But cancer cells escapes normal cell death and continue to
accumulate in the body.
 Tumor cells develops a variety of strategies to escape apoptosis.
 Cancer cells acquires anti apoptotic regulators :-
 Most common is the loss of P53 tumor suppressor function, which
eliminates this critical damage sensor from the apoptosis-
inducing circuit.
 Alternatively, tumors may escape apoptosis by increasing the
expression of antiapoptotic regulators (Bcl-2, Bcl-XL, Mcl1).
 By downregulating proapoptotic Bcl-2-related factors
(Bax,Bim,Apaf-1).

13. 4. LIMITLESS REPRODUCTIVE
POTENTIAL...
1. Mammalian cells have an intrinsic program, the Hayflick
limit, that limits their multiplication to about 60-70 doublings,
at which point they reach a stage of senescence.
2. This limit can be overcome by disabling their pRB and p53
tumor suppressor proteins, which allows them to continue
doubling until they reach a stage called crisis, with apoptosis,
karyotypic disarray, and the occasional (10-
) emergence of an
immortalized cell that can double without limit. Most tumor
cells are immortalized.
3. The counting device for cell doublings is the telomere,
which loses DNA at the tips of every chromosome during each
cell cycle. Many cancers involve the upregulation of

14. 5. SUSTAINED ANGIOGENESIS...
 Angiogenesis is the growth of blood vessels from the existing
vasculature, it is also a fundamental step in the transition of
tumors from a dormant state to a malignant one.
 Cancer cells are cells that have lost their ability to divide in a
controlled fashion. A tumor consists of a population of rapidly
dividing and growing cancer cells.
 Tumors cannot grow beyond a certain size, generally 1-2 mm³,
due to a lack of oxygen and other essential nutrients.
HIF1(Hypoxia inducible factor) act as a transcription factor to
activate the Vascular endothelial growth factor(VEGF).
 To supply nutrients and oxygen, tumors induce blood vessel
growth (angiogenesis) by secreting various growth factors (e.g.
VEGF). Growth factors such as bFGF and VEGF can induce
capillary growth into the tumor.

15. Angiogenesis :
Tumor angiogenesis is the growth of
new blood vessels that supply
tumors with nutrients and oxygen.
Metastasis :
In metastasis, cancer cells break away from
the original (primary) tumor, travel through
the blood or lymph system, and form a new
tumor in other organs or tissues of the body.

16. 6. TISSUE INVASION AND METASTASIS...
 Metastatic cells must mimic normal cell-cell interactions, through
cell-cell adhesion molecules (CAMs) and integrins. N-CAM is normally
adhesive, suppressing metastases, but it becomes altered and allows
metastases in Wilm's tumor, neuroblastoma, and small cell lung
cancer, and its expression is reduced in invasive pancreatic and
colorectal cancers.
 E-cadherin, which is expressed on epithelial cells, transmits
antigrowth signals. E-cadherin is therefore a widely acting
suppressor of invasion and metastasis by epithelial cells, which must
be overcome by cancer cells to progress.
 Integrins display substrate preferences, and changes in integrins are
displayed by migrating cells.
 Matrix-degrading proteases are also necessary to facilitate invasion
into stroma, across blood vessel walls, and through epithelial cell
layers.

17.  FOUR “HALLMARKS OF CANCER” ,WHEN HANAHAN
AND WEINBERG AGAIN REDEFINED IN 2011.

18. 1. DEREGULATED METABOLISM...
 A fundamental change in the metabolism of all four major
classes of macromolecules (carbohydrates, proteins, lipids,
and nucleic acids).
 Genes for glycolysis are overexpressed in the majority of
cancers.
 Potential metabolic therapies include dietary restriction,
which naturally lowers glucose levels and has been shown to
significantly reduce growth and progression of numerous
tumor types including mammary. brain, pancreas, lung, and
prostate. Dietary restriction has the potential to be a broad
spectrum, nontoxic therapy that targets multiple signaling
pathways at once.
6-amino-nicotinamide-a G6PD inhibitor
dichloroacetate (DCA)- a PDK inhibitor

19. 2. INSTABILITY IN GENOMIC DNA...
 An increased tendency of alterations, in the form of
mutations and rearrangements, to the genome of cancer
cells.
 Stepwise, nested generation of hierarchical among-cell
genetic, epigenetic, cytogenetic diversity leading to
evolution of six hallmarks of cancer via mutation,
epimutation, chromosomal alterations.
 Evolution in response to selective pressures including
immune system, 'competition' between cells, cooperation
between cancer cell lineages.
 Origin of genomic instability, leading to much higher
mutation rate.

20. 3. ROLES OF THE IMMUNE SYSTEM IN
CANCER DEVELOPMENT…
 The key functions of the mammalian immune system:
(1) Protect from infectious pathogens.
(2) Monitor tissue homeostasis > Eliminate damaged cells or tumor cells.
 Mechanisms against cancer development:
(1) Cellular immunity- T, NK, & Other innate immune cells.
(2) Humoral immunity- Cytokines
 Mechanisms promoting cancer development:
(1) Inflammation = Angiogenesis & Tissue remodelling.
(2) Enhance survival pathways (NF-kB).
(3) Suppression of anti-tumor immune responses.
 Altered interactions between adaptive and innate immune cells can lead
to "chronic inflammatory disorders".
 Chronic inflammatory conditions enhance a predisposition to

21. 4. INFLAMMATION - A KEY FACTOR
FOR CANCER…
 Inflammation can contribute to multiple hallmark
capabilities by supplying bioactive molecules to the tumor
microenvironment, including growth factors that sustain
proliferative signaling, survival factors that limit cell
death, pro-angiogenic factors, extracellular matrix-
modifying enzymes that facilitate angiogenesis, invasion
and metastasis, and inductive signals that lead to
activation of Epithelial-mesenchymal transitions(EMTs)
and other hallmark-facilitating programs.
 Additionally, inflammatory cells can release chemicals,
notably reactive oxygen species, that are actively
mutagenic for nearby cancer cells, accelerating their
genetic evolution toward states of heightened malignancy.

22.  Role of chronic inflammation in promoting cancer development

23.  SUMMARY…
Cancer should be viewed as A genetic disorder and
also A metabolic disease.
It is considered that defective apoptosis and
successive angiogenesis are a feature of malignant
development.
Induction of apoptosis and suppression of glycolysis
and angiogenesis in malignancies is to be aimed.

24. REFERENCES…
 Hanahan, Douglas, and Robert A Weinberg. 2000. "The
Hallmarks of Cancer Review University of California at San
Francisco.“
 " Hanahan, Douglas, and Robert A Weinberg. 2011. "Review
Hallmarks of Cancer : The Next Generation."
 https://www.slideshare.net/