Chapter 33: TUMOR IMMUNOLOGY

Reporters:
Paglinawan, M.C.
Magarang, Melanie

Oncology is the branch of medicine devoted to the study and treatment of tumors.
Tumor
o A proliferation of cells that produces a mass rather than a reaction or inflammatory condition.
o Tumors are neoplasms and are described as benign or malignant.

Cancer Stem Cells

3 distinctive properties of stem cells:
1. Self-renewal when daughter cells retain the same biologic properties as the parent cell.
2. Capability to develop into multiple lineages.
3. Potential to proliferate extensively.

TYPES OF TUMORS:

Benign Tumors
A tumor that are not cancerous and lacks the ability to invade neighboring tissue or metastasize.
Adenomas benign tumors arising from glands.
Papillomas benign tumors arising from epithelial surfaces.
Characteristics of benign tumors
1. Usually are encapsulated
2. Grow slowly
3. Usually are nonspreading
4. Have a minimal mitotic activity
5. Resemble the parent tissue
Malignant Tumors
A tumor that are cancerous and are made up of cells that grow out of control.
Carcinoma or cancer malignant neoplasm of epithelial origin
1. Squamous cell carcinomas those arising from squamous epithelium
2. Adenocarcinomas those arising from glandular epithelium
3. Transitional cell carcinomas those arising from transitional epithelium in the urinary
system.
4. Neuroendocrine tumors that commonly develop from neural crest and neural ectoderm.
5. Sarcoma malignant tumors of connective tissue origin
6. Teratoma are derived from all three germ layers
Characteristics of malignant tumors
1. Increase in the number of cells that accumulate
2. Usually, invasion of tissues
3. Dissemination by lymphatic spread or by seeding within a body cavity
4. Metastasis
5. Characteristic nuclear features
6. Receptors for integrin molecules which help malignant cells adhere to extracellular matrix
7. Secretion of TGF-alpha and TGF-beta to promote angiogenesis and collagen disposition
Cancer stems cells can be the source of all malignant cells in primary tissue
1. The capacity of self-renewal
2. The potential to develop any cell in the overall tumor population
3. The proliferative ability to drive continued expansion of the population of malignant cells

EPIDEMIOLOGY

Cancer in adults:
Men: Prostate, lung and bronchus, colorectal
Women: Breast, lung and bronchus, and colorectal
Cancer in children:
Acute lymphoblastic leukemia
Risk Factors
Smoking
High fat, low-fiber diet
Obesity
Sedentary lifestyle
Family history
Survivors of childhood and adolescent cancer

CAUSATIVE FACTORS OF HUMAN CANCER

Environmental Factors (Table 33-1)

Aerosols
Industrial pollutants
Drugs
Infectious agents
Radiation
UV light
Note: Cytochrome P-450 an enzyme that activates inactive chemical carcinogens in their native
state.
Host Factors and Disease Associations (Table 33-2)
 Presence of certain genetic disorders ( e.g. Down syndrome)
Cryptorchidism and Klinefelters syndrome
Immunodeficiency syndrome
Viruses (Table 33-1)

STAGES OF CARCINOGENESIS (Box 33-1)

1. Initiation irreversible mutations involving proto-oncogenes

2. Promotion growth enhancement to pass on the mutation of other cells
3. Progression development of tumor heterogeneity for metastasis

CANCER-PREDISPOSING GENES

Cancer-predisposing genes may act in the following ways

Affect the rate of which exogenous precarcinogens are metabolized to actively carcinogenic forms that
can damage he cellular genome directly.
Affect a hosts ability to repair resulting damage to DNA
Alter the immune ability of the body to recognize of the body to recognize and eradicate incipient
tumors.
Affect the function of the apparatus responsible for the regulation of normal cell growth and associated
proliferation of tissue.
Example: BRCA2 breast cancer; APC colon cancer

PROTO-ONCOGENES

A normal gene that can become an oncogene, either after mutation or increased expression.
Acts as a central regulators of the growth in the normal cells that code for proteins involved in growth and
repair processes of the body.
Tumor suppressor genes (antioncogenes)
Normally counteract proto-oncogenes by encoding proteins that prevent cellular differentiation
Are guardians of unregulated cell growth
p53 gene (tumor suppressor gene)
Produces a protein that downregulates the cell cycle
A key responder to various stresses, including DNA damage, hypoxia, and cell aberrations.
The central role of p53 in tumor suppression is to mediate the response of DNA damage.

ROLE OF ONCOGENES (Table 33-4)

The genetic targets of carcinogens

The altered versions of normal genes
Once an oncogene is activated by mutation, it promotes excessive or inappropriate cell proliferation.
Major classes of oncogene products involved in the normal growth processes.
Growth factors
Epidermal growth factors (EGFRs)
Membrane associated protein kinases
Membrane-related guanine triphosphate
Cytoplasmic protein kinases
Transcription regulators located in the nucleus
Mechanisms of Activation
Overexpression of the c-erbB-2 (HER2/neu) oncogene
Activation of the ras-proto-oncogene
Translocation of the abl proto-oncogene
Inactivation of suppressor gene
Viral Oncogenes (Box 33-2)
RNA leukemia , carcinoma, viruses, mammary tumor viruses
DNA herpesviruses, adenoviruses, papilloma viruses

BODY DEFENSES AGAINST CANCER

Tumor immunity has the following general features:

1. Tumors express antigens that are recognized as foreign by the immune system of the tumor-bearing
host.
2. The normal immune response frequently fails to prevent the growth of the tumors
3. The immune system can be stimulated to kill tumor cells and rid the host of the tumor
Host defense mechanisms against tumors are both humoral and cellular. Effector mechanisms:
T lymphocytes
Cytolytic T lymphocyres (CTLs) provide effective antitumor immunity in vivo
Tumor-infiltrating lymphocyte mononuclear cells derived from the inflammatory infiltrate
in human solid tumors. With the capacity to lyse the tumor.

Natural Killer cells

Same lytic mechanism as CTLs to kills and they have broad range of specificities.
Play a role in immunosurveillance against developing tumors.
Macrophages
Produces tumor necrosis factor (TNF) that can kill tumors by direct toxic effects and
indirectly effects on tumor vasculature.
Antibodies
Serves as tumor markers against various tumor antigens
 The rapid growth of a tumor overwhelm the effector mechanisms of the immune response.

TUMOR MARKERS

Are substances present in or produced by tumors that can be used to detect the presence of cancer based on
their measurement in blood, body fluids, cells, or tissue.
Bence-Jones protein the earliest identified tumor marker. (Multiple Myeloma)
Categories of Tumor Antigens:
Tumor-Specific Antigens (TSAs)
Chemically induced tumors
Tumor-Associated Antigens (TAAs)
Virally induced tumors
Carcinofetal Antigens
Are antigens that typically present only during fetal development
Example: Carcinoembryonic Antigen
Spontaneous Tumor Antigens
Tumors caused by no known mechanism

TEN TUMOR MARKERS:

1. Alpha-fetoprotein- a reliable marker for following a patients response to chemotherapy and radiation
therapy.
2. CA 125- a mucin-like glycoprotein.
-most useful in ovarian and endometrial carcinomas.
3. Human epididymis protein 4 for monitoring patients for recurring epithelial ovarian cancer.
4. Thyroglobulin (Tg) to monitor cancer recurrence because of rising levels over time following thyroid
surgery.
5. Prostate-specific antigen and prostatic acid phosphatase-
Prostate-specific antigen (PSA) is a prostate tissue-specific marker. The serum PSA level is directly
proportional to tumor volume.
free PSA assist in distinguishing cancer of the prostate from benign prostatic hypertrophy (BPH). Other
techniques that have been used for detection of prostate cancer:
PSA velocity
PSA density
age-adjusted PSA
free and total PSA
complexed PSA
human kallikrein II (hK2)
Prostatic acid phosphatase- another older marker for prostate cancer.
hK2- alternative marker
early prostate cancer antigen-2 (EPCA-2)- can specifically identify prostate cancer and
distinguish aggressive from nonaggressive disease.
6. Carcinoembryonic antigen - used clinically to monitor progress in patients who have diagnosed cancer with
a high blood CEA level.
It is elevated in patients with colon cancer and was later found to be elevated also in patients with
breast, lung, liver and pancreatic cancer.
Plasma levels higher than 12 ng/mL are strongly correlated with malignancy.
20% of smokers and 70% of former smokers have elevated CEA levels.
7. CA 19-9- is a glycolipid, Lewis blood group carbohydrate. GI cancer-associated antigen
Its main use is as a marker for colorectal and pancreatic carcinoma.
Elevated levels have been found in patients with: pancreatic hepatobiliary, colorectal, gastric,
hepatocellular, pancreatic, and breast cancers.
8. CA 15-3- to monitor patients after mastectomy.
The detection is only 5% for stage 1 breast cancer.
It is also positive in liver disease, some inflammatory conditions and other carcinomas.
9. CA 27.29: breast carcinoma-associated antigen- for predicting early recurrence of breast cancer.
10. HER2/neu- to asses tumor susceptibility to therapy such as lapatinib and trastuzumab.
Evaluation for HER2/neu has two clinical functions:
1. Predictive marker for response to trastuzumab therapy.
2. Prognostic marker.
Trastuzumab
IMC-225

OTHER CANCER BIOMARKERS

1. -human chorionic gonadotrophin (-beta subunit)- Is an ectopic protein. sensitive tumor marker with a
metabolic half-life of 16 hours.
2. Miscellaneous Enzyme Markers
Lactic dehydrogenase (LDH) is a frequently measured enzyme of the glycolytic pathway.
Neuron-specific enolase is an isoenzyme specific for all tumor cells derived from the neural crest.
Placental alkaline phosphatase (ALP) can be detected during pregnancy.
3. Miscellaneous hormone marker
Adenocorticotropic hormone (ACTH), calcitonin and catecholamines.
Oat cell carcinomas may produce -hCG, ADH, serotonin, calcitonin, PTH, and ACTH.
 MOLECULAR DIAGNOSIS OF BREAST CANCER

Assessment of DNA content (aneuploidy, diploid)

Cell cycle analysis (GOG1, S, GS, M)
Dual ISH- Genetic test, determine whether breast cancer proteins are HER2-positive.

BLADDER CANCER
clinical use: Matritech nuclear matrix protein (NMP-22) and Brads BTA test.
Telomerase a growth enzyme that promotes the malignant proliferation of cancer.

MONOCYTE CHEMOTACTIC PROTEIN (MCP-1).

DNA MICROAARAY TECHNOLOGY
Microarrays have the potential to uncover signature gene expression.

NEXT GENERATION SEQUENCING (NGS)

three aspects of importance in NGS are:
1. Identification of somatic mutations.
2. Detection of low levels of genomic alterations.
3. Improved management of cancer treatment.
The goal of NGS technology is to be able to quickly generate data from a small sample of tissue from a
tumor.

Antitumor drugs may be placed in the following three classes:

Cell cycle active, phase-specific
Cell cycle active, phase-nonspecific
Non-cell cycle active

Cell cycle active, phase-specific

they act on the S, G2, or M phase of mitosis.

S phase-active drugs: Antimetabolites

Antifolates
Synthetic enzyme inhibitiors.
G2 phase: bleomycin
Etoposide
M phase: vinca alkaloids
paclitaxel

Cell cycle active, phase-nonspecific

Intercalating agents
alkylating agents
5-fluorouracil

Non-cell cycle active

Alkylating agents
-asparaginase
corticosteroids
hormone antagonists
miscellaneous
CYTOKINES that used to treat certain types of cancer:
IFN, IL-2 and CSFs
Anti-CD20 rituximab- used to relapse indolence lymphoma.

Whats new in Drug therapy?

Imatinib- a potent inhibitor of the Abelson (ABL) kinase in chronic myeloid leukemia (CML).