A presentation descripes tumors,pathogensis,devlopment,antigenes and genes.
how host responds to them and how tumors evade immunity with latest lines of therapy and prevention.
facaulity of pharmacy.Damascus university.master of libaratory diagnossis. immunology.
Baraa ALomar and feras deban
3. Cancer is one of the leading causes of mortality,
morbidity, and decreased quality of life.
Incidence of cancers is growing
It would be the main source of burden on both
patients and societies
Introduction
4. New cancer cases were estimated to be 12.7
million in 2008 whereas it is expected to rise to
22.2 million in 2030.
Accounting for 13 % of all deaths worldwide,in
2008, about 7.6 million died from cancers
About 70 % of overall cancer deaths occurred in
low- to medium resource countries
Incidence, Morbidity and Mortality of
Cancers
5. Incidence of cancers
Estimated age-standardized incidence of overall cancers per 100,000 in different countries
Adapted from ‘Cancer Immunotherapy
for Organ-Specifi c Tumors’
6. Effected factors
Aging Immune
deficiency
Leukemia is the most common cancer
in childhood lung, breast, prostate, and
colorectal cancers are the most
common cancers in adults
Adapted from ‘Cancer Immunotherapy
for Organ-Specifi c Tumors’
8. Introduction
In some pathologic conditions
Cell proliferation exceeds the requirement for cell
replacement
Organ hypertrophy from polyclonal expansion of cells
Once the signal terminates the rate of proliferation
decreases and hypertrophy resolves
12. Non-malignant or malignant
Individual cell may undergo a transforming
event
proliferate independent of external
growth and regulatory signals
Locally invade and disrupt normal tissues
and metastases in distant organs
Malignant
tumors
14. Carcinomas
• (>80%)
• Endodermal or
ectodermal
tissues
• Colon, breast,
prostate, and
lung carcinomas
Lymphomas&
leukemias
• Hematopoietic
cells of the bone
marrow
Sarcomas
• Less frequently
• Mesodermal
connective
tissues such as
bone, fat, and
cartilage
cancers are classified to
15. 1- Induction of cellular proliferation
2- Inhibition of tumor suppressor genes
3- Regulation of programmed cell death
Cancer-associated genes can be
divided into
16. Some encode proteins that induce cellular
proliferation
•Some of these proteins function as growth
factors or growth factor receptors.
•sis encodes a form of platelet-derived growth
factor, and ERBB2 /neu growth-factor receptors
Induction of cellular proliferation
17. In normal cells, the expression of growth factors and
their receptors is carefully regulated.
Inappropriate expression of either a growth factor or
its receptor can result in uncontrolled proliferation.
Induction of cellular proliferation
18. Some encode products that function in signal-
transduction pathways or as transcription factors.
•The p21 oncogene encodes Ras subfamily proteins ;GTP-
binding protein ,which act as signal transducers.
• The myc oncogene encode transcription factor which
plays a role in cell cycle progression and apoptosis.
Overactivity of any of
these oncogenes may
result in unregulated
proliferation
Induction of cellular proliferation
19. Tumor suppressor genes, or anti-oncogenes
• Encodes proteins that inhibit excessive cell
proliferation.
• Inactivation of these genes results in
unregulated proliferation
Inhibition of Tumor suppressor genes
20. An important tumor suppressor gene
which encodes a nuclear
phosphoprotein.
More than half of all human cancers do,
in fact, harbor p53 mutations and have
no functioning p53 protein
P53
Inhibition of Tumor suppressor genes
21. These genes encode proteins that either
block or induce apoptosis.
bcl-2: an anti-apoptosis gene.
Epstein-Barr virus EBV contains a gene that has sequence
homology to bcl-2 and may act in a similar manner to
suppress apoptosis.
Regulation of programmed cell death
29. All tumors induced by a given virus should
carry the same surface antigen,
irrespective of their cellular
origin
Virally controlled antigens
30. Expression of normally silent genes
The dysregulated uncontrolled cell division of the
cancer cell creates a milieu in which the products of
normally silent genes may be expressed.
31. Mutant antigens
hsps may influence the capacity of the tumor
cell itself to process and present endogenous
mutated and 'silent' antigens as targets for specific
T-cells.
http://www.frontiersin.org/files/Articles/13858/fonc-01-00037-r4/image_m/fonc-01-00037-g001.jpg
32.
33. Immunosurveillance theory
Immune system is able to identify transformed
cells and eliminate them.
Incidence of cancer would increase, or the latency
period of cancer would decrease, in the absence of
a functional immune system.
34. Immunosurveillance theory
The tumors that do face immune pressure are virus-
associated cancers and cancers expressing
immunogenic tumor antigens
Most cancers escape immunosurveillance because
they are fundamentally “self”
35. The immunosurveillance hypothesis states that a
physiologic function of the immune cells is to
recognize and destroy transformed cells
Cancer was noted to be increased in patients
receiving long-term immunosuppression because
of a solid-organ transplant
Immunosurveillance theory
36. EX:
HIV-associated immunosuppression has been
linked to a greater increase in cases of Kaposi
sarcoma, non-Hodgkin’s lymphoma, and
invasive cervical cancer.
Immunosurveillance theory
37. Tumor cells Are Often recognized and eliminated through T-cell–
mediated immunosurveillance
Immunosurveillance theory
http://www.amgenoncology.com/disease-state-education/redirecting-t-cells.html
38. Tumors are more frequent in immunodeficient patients.
Transplanted patients ,who made immunosupressor
treatments present a higher incidence of tumors.
Cancer is more likely to appear in advanced ages , when the
immune system is lesser effictive .
Anti-tumor immunosurveillance
evidence
41. • Immune suppression in the tumor
microenvironment, mediated by
CD4+/CD25+ regulatory T cells
(Tregs) seems to be a major
mechanism of tumor immune escape
Regulatory cells
Factors that tumors exploit to
avoid immune responses
42. Factors that tumors exploit to
avoid immune responses
•transforming growth factor
(TGF)-β, produced by tumor
cells, aids conversion of CD4+
T cells into suppressive Tregs
in situ.
Regulatory cells
43. Defective antigen presentation
•Down-modulating antigen processing
machinery affecting the major
histocompatibility complex (MHC) I
pathway.
Factors that tumors exploit to
avoid immune responses
44. Defective antigen presentation
•expression of tumor antigen is downregulated,
which can lead to enhanced tumor incidence
and metastasis because cytotoxic T
lymphocyte (CTL) can no longer recognize
target antigens on the tumor cells
Factors that tumors exploit to
avoid immune responses
45. Immune suppressive mediators
Cancer produce several immune suppressive
cytokines that suppresses CTL function .
TGF-β is a chief mediator of this activity, tumor
necrosis factor (TNF)-α, IL-1, IL-6, colony stimulating
factor (CSF)-1, IL-8, IL-10.
Factors that tumors exploit to
avoid immune responses
46. Immune suppressive mediators
Vascular endothelial growth factor (VEGF) inhibit maturation of
DCs, thus affecting efficient uptake and antigen presentation.
Factors that tumors exploit to
avoid immune responses
50. Chemotherapy
Alkylating agents:
• Work in all phases of the cell cycle
• Carboplatin, Cisplatin , Cyclophosphamide
Antimetabolites
• Interfere with DNA and RNA growth
• 5-fluorouracil (5-FU) 6-mercaptopurine (6-
MP)…..
Chemotherapy
works with the
cell cycle .
damaging the
DNA
51. Anti-tumor antibiotics
• changing the DNA inside cancer cells to keep them
from growing and multiplying.
• Daunorubicin , Doxorubicin Actinomycin-D
Bleomycin, Mitomycin-C
Chemotherapy
53. Act on specific molecular targets that are associated with cancer
Targeted therapies are often cytostatic whereas standard
chemotherapy agents are cytotoxic
Trastuzumab (Herceptin®): which is approved to treat certain breast and stomach cancers
that overexpress HER-2.
Targeted Cancer therapies
54. Targeted Cancer therapies
Hormone therapies
• slow or stop the growth of hormone-sensitive tumors
Gene expression modulators
• modify the function of proteins that play a role in controlling gene
expression.
Apoptosis inducers
• cause cancer cells to undergo a process of controlled cell death called
apoptosis
55. Immunotherapies
• trigger the immune system to destroy cancer cells
Monoclonal antibodies that deliver toxic molecules
• can cause the death of cancer cells specifically.
Targeted Cancer therapies
56. Preventive (or prophylactic) vaccines
• Stimulate the production of antibodies that bind to
specific targeted Cancer-causing viruses and block their
ability to cause infection.
• (hepatitis B virus and human papillomavirus)
Vaccination therapy
57. Preventive (or prophylactic) vaccines
• Human papillomavirus (HPV) vaccines
Cervarix®
• Hepatitis B virus (HBV) vaccines
Engerix-B®
Vaccination therapy
58. Treatment (or therapeutic) vaccines
• strengthening the body’s natural immune response
against the cancer.
• prostate cancer vaccine: stimulate an immune response to
prostatic acid phosphatase (PAP).
• EX: Provenge®.
Vaccination therapy
59.
60. • Differences between malignant and non malignant
tumors.
• The effected factors in cancerous state.
• Types of Tumors genes.
• Relationship between P53 and cancer development.
Message to take home
63. • http://journal.frontiersin.org/article/10.3389/fonc.2011.00037/full
(Accessed 14/7/2016)
• http://www.ncbi.nlm.nih.gov/books/NBK9557/ (Accessed
14/7/2016)
• Aryan.Z , Mellstedt.H , Rezaei,R. Cancer Immunotherapy Confers 1
a Global Benefit in (Cancer Immunotherapy for Organ-Specifi c
Tumors). Rezaei.N,springer 2015.(45-84)
• Ivan M, Roitt and Peter J.Develes. Tumor immunology in (ROITT’S
essential immunology).Peter J. Develes. Blackwell science
(10).2007..384-394
References
on tumor cells
(TSTAs) unique to tumor cells and do not occur on normal cells
They may result from mutations in tumor cells that generate altered cellular proteins; cytosolic processing of these proteins would give rise to novel peptides that are presented with class I MHC molecules, inducing a cell-mediated response by tumor-specific CTLs.
TATAs not unique to tumor cells
may be proteins that are expressed on normal cells during fetal development
proteins that are normally expressed at extremely low levels on normal cells
فيروسُ القِرْدِيُّ 40 هو فيروس تورامي من فيروسات الدنا يصيب السعادين والإنسان حيث يتسبب بأورام لكن في معظم الأحيان يمر كعدوى كامنة.
Elimination—Immune cells mount the initial antitumor response. Equilibrium—Insufficient elimination enables developing tumor to acquire tumor evasive mechanisms Escape—Tumor cell evasion results in cancer progression
بامكاننا استغلال هذه النقطة في تشكيل اضداد وحيدة النسيلة ضد CD25 (basiliximab) لتقوم بقتل ال Tregs .
Indoleamine 2,3-dioxygenase (ido)
Lymphocytes are said to be anergic when they fail to respond to their specific antigen
Fas احد مستقبلات نقل الاشارة و يحرض الاستموات
These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied
Mitotic inhibitors الانقسام الفتيلي