Major Credit Seminar
On
Advancements in Cancer
Research with Special
Reference to Pathogenesis
and Diagnosis
Presented
by
...
Present Cancer Scenario..
• Out of the total deaths in world 12-13 % deaths are due to
cancer..
• In world 8.2 million peo...
“ An abnormal mass of tissue, the growth of which
exceeds and is uncoordinated with that of the normal
tissues and persist...
TYPES OF NEOPLASM
BENIGN NEOPLASMS
Designated by the suffix – ‘oma’
• Adenoma – glandular epithelium
• Papilloma – epithel...
CLASSIFICATION/NOMENCLATURE
HISTOGENIC CLASSIFICATION
Based on the origin of neoplastic cell types.:
• Mesenchymal tumours...
Tissue of origin Benign Malignant
A)Tumors of mesenchymal
origin
1.Connective tissue and
derivatives
Fibroma
Lipoma
Chondr...
DEVELOPMENT
OF
CANCER
METALOPROTINEASEMETALOPROTINEASE
Development of malignant tumour
Less than 10 mutation required
Etiology of cancerEtiology of cancer
Intrinsic factors
• HEREDITY
• AGE
• PIGMENTATION
. SEX
. TUMOUR IMMUNITY
EXTRINSIC F...
Environmental Carcinogens
• A cancer-causing agent
• Three main types:
– Chemical
– Physical (radiation)
– Biological (esp...
How Cancer Arises
1. Cancer cells violate the civic rules that govern normal
cells by not responding to go-signals for pro...
Molecular Basis of Cancer
• Tumors are monoclonal
proliferation
• Tumors carry genetic
defect that are not lethal
(inherit...
What are the genes involved in Cancer?
• A lot of genes!
• Like what?
• Genes promote growth eg. RAS
• Genes inhibit growt...
Current gene list and technology
Knudsen’s “two- hit”
hypothesis
Two separate
mutations, one
in each allele of
a tumor
suppressor
gene, are needed
to cause...
18
How cellular oncogenes arise
Cellular oncogenes arise from proto-oncogenes
Proto-oncogenes are not bad genes.
Normal ...
• Targeted genes:
– 1. Proto-oncogenes (oncogenes)
– 2. Tumor suppressor genes
– 3. Genes controlling apoptosis
– 4. Genes...
What does a cell need to be “cancer”?
The hallmark of cancer
1. ONCOPROTEIN
2. RB GENE
3. BAX gene
4. TELOMERASE
5. VEGE, ...
Most cells are quiescent and are in the G0 (inactive) part of the cell cycle
Most adult cells are NOT actively dividing
Mu...
G1
S
RB
Adenovirus E1A
HPV E7
SV40 Lg T
APOPTOSIS
p53
Adenovirus E1B(55K)
HPV E6
SV40 Lg TAdenovirus E1B (19K)
(Bcl2-like)...
Molecular basis of cancer
Classification of oncogenes
1. Growth factors – c sis,
2. Growth factor receptors
(RTK) - ERBB2, fms
3. Non receptor tyros...
How Cellular Oncogenes ArisePoint
mutation
.
Tumor suppressor: Gene that normally inhibits tumor formation; mutation or poor
expression releases the inhibition
MDM2 ,triggers transcription for many gene
Key tumor suppressor genes are mutated
Molecular Policeman
BRCA1 and BRCA2, two famous genes whose mutations confer a high increased risk of breast
cancer on carriers, are both asso...
Early detection is the key!
Cancer diagnosis comprises
of
.involves evaluation of the patient’s history,
 clinical examinations
paraneoplastic diso...
Stage 0: carcinoma in situ.
Stage I: cancers are localized to one
part of the body
Stage II: cancers are locally advanced....
Grade
GX Grade cannot be assessed (Undetermined grade)
G1 Well-differentiated (Low grade)
G2 Moderately differentiated (In...
IMAGING
 Malignancy is based on imaging information ,later confirmed on
histology
 Ultrasound (kondyo et al.,2008)
Comp...
Cytology and Histopathological Technique
1. Still a gold standard for diagnosis of tumour.
Recent technique 
 Imaging
IH...
• What is tumor marker?
 Tumor markers are glycoproteins
produced by tumor cells or by other
body cells in response to ca...
Sr.Sr.
No.No.
Disease/TissueDisease/Tissue MarkersMarkers
11 Bladder cancerBladder cancer BTA, NMP22, CEA, CA125, CA19-9BT...
• Ag –Ab based Techniques :
i) ELISA
ii) Radio-immunoassay
iii) Flow Cytometry
iv) Immunohistochemistry
• Molecular Geneti...
Immuno-histochemistry  has  been  utilized  extensively  to 
determine estrogen, progesterone and Her-2 neu receptor stat...
Immunohistochemistry (IHC)
• Ag + [Ab + fluorescent dye]
• Detection of protein of tumors
by using specific antisera &
MCA...
A single gene chip can even hold representative fragments from the entire human
genome.
Different microrray labeling kit
• Present in perfectly normal conditions
• Act as chaperones making sure that
the cell’s proteins are in the right shape
a...
• For normal function
of p53 it require
transient interaction
of Hsp 90 and then
degraded
• Mutation of p53
• Mutated p53 ...
• Over-expression of HSP70 and HSP90
correlates with a bad prognosis of tumor
• Overexpression of HSP27 in leukemia
osteos...
According to the US National Cancer Institute (OTIR, 2006)
“Nanotechnology willchange the very foundations of cancer diagn...
. Nanotechnology will make possible to run test without physically
altering the cells or tissue
Cancer nanotechnology is emerging as a new field of interdisciplinary
research, cutting across the disciplines of biology, ...
Nanodevices Are
Small Enough to Enter Cells
Cell
White
blood cell
Water
molecule
Nanodevices
Nanodevices
Nanodevices Can Improve Cancer
Detection and Diagnosis
ImagingNanotechnology Physical Exam,
Symptoms
Nanodevices Can Improve Sensitivity
and determine
which cells are
cancerous or
precancerous.
Precancerous cells
Normal cel...
Nanodevices Can
Preserve Patients’ Samples
Cells from patient
Cells preserved
Active state preserved
Cells altered
Active ...
Nanodevices Can Make Cancer Tests
Faster and More Efficient
Patient A Patient B
Laser Capture Microdissection
Cancer prevention
Conclusion
1.Histopathology remains the standard conventional
method.
2. Recent technique such as imaging ,ICH ,PCR ,flow
...
Cosmic Energy essential to maintain the order of our life and expand
our consciousness, it is base for our all action and ...
Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis
Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis
Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis
Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis
Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis
Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis
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Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis

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Cancer is a major human and animal health problem worldwide and is the second leading cause of death in the world wide. Over the past 30 years .significant progress has been achieved in understanding the molecular basis of cancer. The accumulation of this basic knowledge has established that cancer is a variety of distinct disease and that defective gene cause this disease. Further gene defect are diverse in nature and can involve either loss or gain of gene function.

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  • Most animal cells are 10,000 to 20,000 nanometers in diameter. This means that nanoscale devices (less than 100 nanometers) can enter cells and the organelles inside them to interact with DNA and proteins. Tools developed through nanotechnology may be able to detect disease in a very small amount of cells or tissue. They may also be able to enter and monitor cells within a living body.
  • Detection of cancer at early stages is a critical step in improving cancer treatment. Currently, detection and diagnosis of cancer usually depend on changes in cells and tissues that are detected by a doctor’s physical touch or imaging expertise. Instead, scientists would like to make it possible to detect the earliest molecular changes, long before a physical exam or imaging technology is effective. To do this, they need a new set of tools.
  • In order to successfully detect cancer at its earliest stages, scientists must be able to detect molecular changes even when they occur only in a small percentage of cells. This means the necessary tools must be extremely sensitive. The potential for nanostructures to enter and analyze single cells suggests they could meet this need.
  • Many nanotechnology tools will make it possible for clinicians to run tests without physically altering the cells or tissue they take from a patient. This is important because the samples clinicians use to screen for cancer are often in limited supply. It is also important because it can capture and preserve cells in their active state. Scientists would like to perform tests without altering cells, so the cells can be used again if further tests are needed.
  • Miniaturization will allow the tools for many different tests to be situated together on the same small device. Researchers hope that nanotechnology will allow them to run many diagnostic tests simultaneously.
  • Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis

    1. 1. Major Credit Seminar On Advancements in Cancer Research with Special Reference to Pathogenesis and Diagnosis Presented by Dr. Rahul G. Kadam Ph.D Scholar
    2. 2. Present Cancer Scenario.. • Out of the total deaths in world 12-13 % deaths are due to cancer.. • In world 8.2 million people died due to cancer during 2013. • By 2030 deaths are expected to rise up to 12.0 million. • The cancer deaths are exceeding the cardiac deaths. • Every day 2000 peoples died by cancer worldwide. • Among all these losses 40 % deaths can be avoided by early diagnosis and according treatment.
    3. 3. “ An abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner even after cessation of the stimuli that evoked the change.” New growth composed of cells originally derived from normal tissues, that have undergone heritable genetic changes allowing them to become relatively unresponsive to normal growth controls and to expand beyond their normal anatomical boundaries. Cancer
    4. 4. TYPES OF NEOPLASM BENIGN NEOPLASMS Designated by the suffix – ‘oma’ • Adenoma – glandular epithelium • Papilloma – epithelial tumor forming finger like projections with a connective tissue core MALIGNANT NEOPLASMS • Sarcoma – from mesenchymal tissue • Carcinoma – from epithelial tissue
    5. 5. CLASSIFICATION/NOMENCLATURE HISTOGENIC CLASSIFICATION Based on the origin of neoplastic cell types.: • Mesenchymal tumours: Arise in cells of embryonic mesoderm Benign – oma; malignant – sarcoma • Epithelial tumours: Glandular – adenoma/adenocarcinoma Squamous / basal • Non epithelial: fibrous, cartilage, bone, muscle, etc Some tumors have more than one parenchymal cell type – Mixed tumors –derived from a single germ cell layer that differentiates into more than one cell type. – Teratomas – made of a variety of parenchymal cell types that derive from more than one germ cell layer formed by totipotent cells that are able to form ectoderm, endoderm & mesoderm.
    6. 6. Tissue of origin Benign Malignant A)Tumors of mesenchymal origin 1.Connective tissue and derivatives Fibroma Lipoma Chondroma Osteoma myxoma Fibrosarcoma Liposarcoma Chondrosarcoma Osteogenic sarcoma myxosarcoma 2.Endothelial and related tissues Hemangioma Lymphangioma Meningioma - Hemangiosarcoma Lymphangiosarcoma Invasive meningioma mesothelioma 3.Tumours of Hematopoietic cells - Lymphoma - - Lymphoid leukaemia Lymphosarcoma Myeloid leukaemia Multiple myeloma 4.Tumours of Muscle Leiomyoma Rhabdomyoma Leiomyosarcoma Rhabdomyosarcoma B)Tumors of Epithelial origin Papilloma - Adenoma melanoma Transititonal cell papilloma - Squamous cell carcinoma Basal cell carcinoma Adenocarcinoma Melano carcinoma Transitional cell carcinoma Seminoma c)Tumours of nervous tissue neuroma neuroblastoma WHO & IARC ,Lyon, 2000
    7. 7. DEVELOPMENT OF CANCER
    8. 8. METALOPROTINEASEMETALOPROTINEASE
    9. 9. Development of malignant tumour Less than 10 mutation required
    10. 10. Etiology of cancerEtiology of cancer Intrinsic factors • HEREDITY • AGE • PIGMENTATION . SEX . TUMOUR IMMUNITY EXTRINSIC FACTOR •CHEMICALS •RADIANT ENERGY •CHRONIC IRRITATION •HORMONE •PARASITES •ONCOGENIC VIRUS Chronic irritation : Kangari, Parasite :Gongylonema.neoplasticum
    11. 11. Environmental Carcinogens • A cancer-causing agent • Three main types: – Chemical – Physical (radiation) – Biological (especially virus) • Direct-acting • Indirect-acting (must be metabolized to activated metabolic forms • Direct-acting carcinogens are already electrophilic • Indirect-acting carcinogens are metabolically activated into electrophilic species
    12. 12. How Cancer Arises 1. Cancer cells violate the civic rules that govern normal cells by not responding to go-signals for proliferation and stop-signals for reproduction 2. Cancer cells descend from a common ancestral cell: clonal origin. But at some point one of the off-springs mutate that becomes worse with more mutation, and finally the accumulated mutated cells disobey all civic controls of normal cells in a tissue, becoming invasive and malign. 3. Since mutations occur at the gene level, that is, DNA molecules that reside in the nuclei of the cells, most human cancer be traced there.
    13. 13. Molecular Basis of Cancer • Tumors are monoclonal proliferation • Tumors carry genetic defect that are not lethal (inherited or acquired) • Transformed cells acquire gene defects that allow them to form tumor
    14. 14. What are the genes involved in Cancer? • A lot of genes! • Like what? • Genes promote growth eg. RAS • Genes inhibit growth eg. P53 • Genes control apoptosis eg. Bcl-2 • Genes of DNA repair • And others…. Functional classification Up regulated genes (%) Down regulated genes(%) Metabolism 21 30 Cell adhesion 4 4 Cell structure 3 6 Immune response 6 9 Functional classification of genes discriminating the normal rat Mammary gland from NMU-induced tumors ( Marsen M.et al., 2005) Oncogenes and tumor suppressors
    15. 15. Current gene list and technology
    16. 16. Knudsen’s “two- hit” hypothesis Two separate mutations, one in each allele of a tumor suppressor gene, are needed to cause cancer
    17. 17. 18 How cellular oncogenes arise Cellular oncogenes arise from proto-oncogenes Proto-oncogenes are not bad genes. Normal genes for regulation of cell proliferation and survival When it change the structure and activity by mutation: causing cancer Gain-of-function mutation
    18. 18. • Targeted genes: – 1. Proto-oncogenes (oncogenes) – 2. Tumor suppressor genes – 3. Genes controlling apoptosis – 4. Genes regulating DNA repair • Other genes involved: – Genes regulating angiogenesis – Genes enhancing invasion and metastasis • Carcinogenesis is a multistep process – At both genetic and phenotypic levels – Progression results from accumulation of genetic defects The cancer –related gene produce six basic change.
    19. 19. What does a cell need to be “cancer”? The hallmark of cancer 1. ONCOPROTEIN 2. RB GENE 3. BAX gene 4. TELOMERASE 5. VEGE, bFGC, THROMBOSPODIN-1 (Sheibani et al.,1999) 6. E-CADHERINS , BETA CATEINS
    20. 20. Most cells are quiescent and are in the G0 (inactive) part of the cell cycle Most adult cells are NOT actively dividing Mutation in one of the four genes that regulate cell cycle. RB.CDK4,CyclinD ,CDKN2A
    21. 21. G1 S RB Adenovirus E1A HPV E7 SV40 Lg T APOPTOSIS p53 Adenovirus E1B(55K) HPV E6 SV40 Lg TAdenovirus E1B (19K) (Bcl2-like) Viral Oncogenes Induce Proliferation and Suppress Apoptosis RB protein unable to bind the E2F DNA viruses can ruin two of the best understood Tumour supressor gene. P53 gene is a monitor of stress.
    22. 22. Molecular basis of cancer
    23. 23. Classification of oncogenes 1. Growth factors – c sis, 2. Growth factor receptors (RTK) - ERBB2, fms 3. Non receptor tyrosine kinases - abl, src 4. GTP binding - RAS 5. DNA damage repair - ATM, MSH2, B cl2 6. Serine/ threonine kinases 7.Nuclear Transcription Factors – MYC,MYB,JUN, FOS 8. Misc - cell surface APC/ DCC Imogene : Gene mutated such that the protein is produced in higher quantity or is more active and initiates tumor formation Imogene : Gene mutated such that the protein is produced in higher quantity or is more active and initiates tumor formation
    24. 24. How Cellular Oncogenes ArisePoint mutation .
    25. 25. Tumor suppressor: Gene that normally inhibits tumor formation; mutation or poor expression releases the inhibition
    26. 26. MDM2 ,triggers transcription for many gene
    27. 27. Key tumor suppressor genes are mutated Molecular Policeman
    28. 28. BRCA1 and BRCA2, two famous genes whose mutations confer a high increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, XERODERMA PIGMENTATION
    29. 29. Early detection is the key!
    30. 30. Cancer diagnosis comprises of .involves evaluation of the patient’s history,  clinical examinations paraneoplastic disorder  review of laboratory test results  radiological data, (X-ray.CT scan ,MRI. Ultrasound imaging)  Biopsy  Cancer staging Diagnostic approaches of tumor.
    31. 31. Stage 0: carcinoma in situ. Stage I: cancers are localized to one part of the body Stage II: cancers are locally advanced. Stage :Whether a cancer is designated as Stage II or Stage III can depend on the specific type of cancer;  Stage IV: cancers have often metastasized, or spread to other organs or throughout the body. TNM SYSTEM COMMONLY USED METHOD OF STAGING BASD ON PRIMARY LESION. .
    32. 32. Grade GX Grade cannot be assessed (Undetermined grade) G1 Well-differentiated (Low grade) G2 Moderately differentiated (Intermediate grade) G3 Poorly differentiated (High grade) G4 Undifferentiated (High grade) The American Joint Committee on Cancer recommends the following guidelines for grading tumors (1):
    33. 33. IMAGING  Malignancy is based on imaging information ,later confirmed on histology  Ultrasound (kondyo et al.,2008) Computed topography,(Drosot et al.,1996) Magnetic resonance imaging(MRI)(kaiser et al 1992) Metabolic and functional Imaging Molecular imaging with magnetic resonance spectroscopy.(MRS) Position emission topography,(PET)(Grahek D et al 2004)
    34. 34. Cytology and Histopathological Technique 1. Still a gold standard for diagnosis of tumour. Recent technique   Imaging IHC PCR Flow cytometary  FISH MICROARRAY NANOTECHNOLOGY
    35. 35. • What is tumor marker?  Tumor markers are glycoproteins produced by tumor cells or by other body cells in response to cancer or other conditions.  As tumor cells multiply, spreads & tissue is damaged TMs increase in concentration. • How it produced? Tumor Markers • Where do the TMs found?  These substances can be found in the blood (plasma, serum), urine, saliva, tissue fluid, in the tumor tissue or in other tissues.
    36. 36. Sr.Sr. No.No. Disease/TissueDisease/Tissue MarkersMarkers 11 Bladder cancerBladder cancer BTA, NMP22, CEA, CA125, CA19-9BTA, NMP22, CEA, CA125, CA19-9 22 Breast cancerBreast cancer CA15-3, CEA, CA27-29CA15-3, CEA, CA27-29 33 Colorectal cancerColorectal cancer CEA, CA 19-9CEA, CA 19-9 44 GestationalGestational HCGHCG 55 Liver cancerLiver cancer AFPAFP 66 Lung CancerLung Cancer CEA, NSECEA, NSE 77 Melanoma sink cancerMelanoma sink cancer TA-90, S100TA-90, S100 88 Multiple myelomaMultiple myeloma B2MB2M 99 Ovarian CancerOvarian Cancer CA125, CA72-4, HCG, AFPCA125, CA72-4, HCG, AFP 1010 Pancreatic CancerPancreatic Cancer CA 19-9, CEACA 19-9, CEA 1111 Prostate CancerProstate Cancer PSA, PAPPSA, PAP 1212 Gastric CancerGastric Cancer CEACEA 1313 Testicular CancerTesticular Cancer HCG, AFP, PAPHCG, AFP, PAP List of commonly used TMs
    37. 37. • Ag –Ab based Techniques : i) ELISA ii) Radio-immunoassay iii) Flow Cytometry iv) Immunohistochemistry • Molecular Genetic Techniques : i) PCR / RT PCR ii) Fluorescence in situ Hybridization ((FISH) iii) Comparative Genomic Hybridization (CGH) • Other Techniques : i) Spectophotometry Tumor Markers detection Methods
    38. 38. Immuno-histochemistry  has  been  utilized  extensively  to  determine estrogen, progesterone and Her-2 neu receptor status  in breast cancer in predicting response to therapy (Diaz, Leslie et al.,2005) Detection of  over expression of c-erbB2 oncoproteins by ICH in  canine mammary tumour.( Mayilkumar K et al ,.2009)   Immuno- histochemistry(IHC) IHC based on specific antigenic determinants in the cell of tissue by use of polyclonal or monoclonal antibodies.(Ramos-Vara et al., 2005) 
    39. 39. Immunohistochemistry (IHC) • Ag + [Ab + fluorescent dye] • Detection of protein of tumors by using specific antisera & MCAb directed against them. • Detection of surface receptors to intracellular matrix to hormone can be detected with ease. • Help ti determine the primary site of metastatic tumor. (Ramos-Vara et al., 2005)
    40. 40. A single gene chip can even hold representative fragments from the entire human genome.
    41. 41. Different microrray labeling kit
    42. 42. • Present in perfectly normal conditions • Act as chaperones making sure that the cell’s proteins are in the right shape and in the right place at the right time. • HSPs also help to shuttle proteins • Transport old proteins to “garbage disposals” /proteasome inside the cell. Heat shock Protein
    43. 43. • For normal function of p53 it require transient interaction of Hsp 90 and then degraded • Mutation of p53 • Mutated p53 have unstableconformation • Extended interaction with Hsp 90 and prevent their normal degradation • Accumulation of mutant p53
    44. 44. • Over-expression of HSP70 and HSP90 correlates with a bad prognosis of tumor • Overexpression of HSP27 in leukemia osteosarcoma ovarian cancer, prostate cancer • Overexpression of HSP70 indicates high grade malignancy
    45. 45. According to the US National Cancer Institute (OTIR, 2006) “Nanotechnology willchange the very foundations of cancer diagnosis, treatment, and prevention” NANOTECHNOLOGY IN CANCER
    46. 46. . Nanotechnology will make possible to run test without physically altering the cells or tissue
    47. 47. Cancer nanotechnology is emerging as a new field of interdisciplinary research, cutting across the disciplines of biology, chemistry, engineering, and medicine, and is expected to lead to major advances in cancer detection, diagnosis, and treatment .(Menon U, Jacobs IJ. 2000, Ferrari M. 2005.) Schematic diagram showing nanotechnology applications in cancer through molecular tumor imaging, early detection, molecular diagnosis, targeted therapy, and cancer bioinformatics
    48. 48. Nanodevices Are Small Enough to Enter Cells Cell White blood cell Water molecule Nanodevices Nanodevices
    49. 49. Nanodevices Can Improve Cancer Detection and Diagnosis ImagingNanotechnology Physical Exam, Symptoms
    50. 50. Nanodevices Can Improve Sensitivity and determine which cells are cancerous or precancerous. Precancerous cells Normal cells Nanodevices could potentially enter cells Precancerous cells Normal cells
    51. 51. Nanodevices Can Preserve Patients’ Samples Cells from patient Cells preserved Active state preserved Cells altered Active state lost Additional tests Cells from patient Nanotechnology Tests Traditional Tests
    52. 52. Nanodevices Can Make Cancer Tests Faster and More Efficient Patient A Patient B
    53. 53. Laser Capture Microdissection
    54. 54. Cancer prevention
    55. 55. Conclusion 1.Histopathology remains the standard conventional method. 2. Recent technique such as imaging ,ICH ,PCR ,flow cytometry ,FISH, CSH ,and microarry nanotechnalogy contribute a major break through in diagnosis prognosis of cancer. 3.In future a multimodal imaging approach will evolve, enhancing diagnostic accuracy thus minimizing loss of lives due to cancer.
    56. 56. Cosmic Energy essential to maintain the order of our life and expand our consciousness, it is base for our all action and functions and to lead healthy and happy life. To remove all disorder of body. More cosmic energy is obtained through MEDITATION.

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