Tumor Markers in Oncology

Immunology & Serology I - 0202308

• Course offered by the Faculty of Health Professions, Department of Medical Laboratory Sciences at Al-Quds University
• Course instructor: Dr. Rasmi Abu-Helu (Ph.D., Immunology)
• Course details provided might be part of larger course material.
• Current presentation topic is Tumor Immunology.

Tumor Immunology - Chapter Overview

• Key topics within Tumor Immunology include:
  • Tumor Biology
  • Tumor Antigens
  • Clinically Relevant Tumor Markers
  • Laboratory Tests for Tumors
  • Immune Defenses Against Tumors
  • Immunoediting and Tumor Escape
  • Immunotherapy

Learning Objectives

• Students will be able to compare benign and malignant tumors
• Students will be able to define and provide examples of proto-oncogenes
• Students will be able to describe oncogene roles
• Students will be able to describe characteristics of major bodily defenses against cancer
• Students will be able to discuss characteristics of tumor markers
• Students will be able to discuss developments in cancer diagnostic testing

Introduction to Tumor Biology

• Tumor (neoplasm) is an abnormal cell mass
• Cancer is a malignant tumor that can spread
• Mutations in proto-oncogenes and tumor suppressor genes cause cancer
• Uncontrolled cell division and other characteristics are present in cancer

Definitions

• Neoplasm: An abnormal mass of tissue resulting from uncontrolled growth of normal cells, even after removing the growth stimulus.
• Benign tumor: Mild, non-progressive tumor that pushes normal tissue aside as it expands without invading it
• Malignant tumor: Composed of poorly differentiated cells that rapidly grow and invade surrounding tissue, depriving normal tissue of nutrients.
• Metastatic tumor: A secondary tumor derived from a malignant primary tumor

Characteristics of Cancer Cells

• Sustained proliferation
• Resist death
• Induce angiogenesis
• Immortality
• Invasion and metastasis
• Avoid suppressors of cell growth
• Altered metabolism
• Evasion of immune defenses
• Genomic instability
• Accelerated growth in the presence of inflammation

Tumor-Associated Antigens

• For the immune system to react to a tumor, the tumor must have antigens recognized as foreign.
• Relevant antigens include enzymes, receptors, and membrane antigens.
• Surface membrane molecules may be antigenic.
• Suppressing membrane proteins essential for immune recognition and activation is also relevant.

Tumor-Specific Peptides

• Intracellular proteins are expressed on tumor cells with MHC class I and II
• This expression can be chemically induced

Virus-Induced Tumors

• Viruses can cause tumors.
• Tumor cells express viral antigens on their surfaces
• Tumor cells are recognized as non-self by the immune system

Genome-Encoded Tumor Antigens

• Oncogenes: If downregulated, their protein product can lead to tumor development.
• Proto-oncogenes: Found in all nucleated cells; involved in cell growth; alteration in gene expression or protein structure may result in abnormal cell growth.

Oncofetal Antigens

• Found on normal fetal cells, but produced in minute amounts after birth.
• Become expressed later after malignant transformation.
• Examples include alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA).
• CEA is found in ~90% of colorectal cancers.

Immunity to Tumors (Natural Immunity)

• Macrophage-mediated cytotoxicity: Macrophages kill tumor cells upon contact
• NK cells: 50% of tumors have mutations that reduce MHC class I on their surfaces, making them susceptible to NK cell killing.

Immunity to Tumors (Humoral Immunity)

• Antibodies can be produced against tumor cell surface antigens.
• Tumor cell lysis occurs via complement activation and antibody-dependent cellular cytotoxicity (ADCC) that involves NK, PMNs (polymorphonuclear leukocytes), and macrophages.

Immunity to Tumors (T-cell Mediated Immunity)

• Cytokines play a role in tumor immunity: IL-1 activates T, B, and NK cells; TNFα destroys tumor cells; interferon-γ (IFNγ) is produced by activated T, B, and NK cells.
• CTLs (cytotoxic T lymphocytes) can directly lyse tumor cells.

Immune Defenses Against Tumor Cells

• A complex interplay of immune cells and components is involved in tumor defense.

Body Defenses Against Cancer

• Immune evasion by tumors—Mutations in MHC genes, antigen-loss variant of tumor cells, and loss of T-cell recognition contribute to this evasion.
  • Production of immunosuppressive proteins & Inhibition of T-cell activation can also occur.

Immunoediting and Tumor Escape

• The immune system's role in eliminating, controlling, or escaping tumor cells is a dynamic process.

Tumor Evasion of Immune System

• Anti-tumor antibodies might block CTL binding sites.
• Tumor cells might express less Class I MHC, preventing CTL-mediated death.
• Tumor cells may provide poor costimulatory signals

Tumor Markers

• Glycoproteins found in small amounts in normal serum, but elevated in certain cancers.
• Used for cancer screening, monitoring therapeutic response, and determining tumor burden.

Carcinoembryonic Antigen (CEA)

• Used in management of gastrointestinal (GIT) tumors, including colon cancer, adenocarcinoma of the colon, pancreas, liver, and lung
• Found in inflammatory bowel disease (IBD), ulcerative colitis, polyps, tumors of GIT, Crohn disease, and cigarette smokers.
• Highest levels are found in metastatic disease.
• Normal CEA levels are up to 2.5 ng/mL in normal people.
• 4–5 times normal levels may indicate colo-rectal tumor recurrence.

α-Fetoprotein (AFP)

• High levels found in patients with hepatocellular carcinoma, hepatoblastoma, testicular and ovarian cancers, viral hepatitis, and cirrhosis, and ulcerative colitis.
• Very important marker in cancer therapy monitoring.
• Normal range is 0-20 ng/mL.
• Monitoring hepatomas and testicular cancers is via a 5-fold or higher rise in this protein.
• Raised levels can be non-malignant, such as due to cirrhosis, hepatitis, and other liver damage.

Human Chorionic Gonadotropin (HCG)

• Composed of α and β subunits (β-HCG)
• Found in serum and urine during pregnancy, produced by neoplastic cells in testicular cancer and other tumors
• Levels of β-HCG aid in evaluating patients with gestational trophoblastic disease, testicular tumors, and ovarian germ cell tumors
• Normal range is < 15 ng/mL in adult men.

Prostate-Specific Antigen (PSA)

• Glycoprotein that dislodges seminal gel after ejaculation.
• Found in very low amounts in the blood of normal individuals
• Increased in prostate cancer, benign prostatic hypertrophy, and acute/chronic prostatitis
• Levels correlate with prostate size, cancer stage, and treatment response.
• Used for prostate cancer screening, often in conjunction with digital rectal examinations.
• Normal PSA levels are below 4 ng/mL.

Clinically Relevant Tumor Markers

• Biological substances found in increased amounts in blood, body fluids, or tissues of cancer patients.
• Serum concentration depends on tumor cell proliferation and size; high levels indicate significant tumor mass.
• Ideally, tumor markers should be highly sensitive and specific.

Clinical Uses of Tumor Markers

• Population screening to identify cancer in asymptomatic individuals (e.g., PSA).
  • Note: Early detection is possible but false positives and negatives can occur.
• Diagnosis to identify cancer in a particular patient (e.g., PSA).

Common Serum Tumor Markers

• Table lists examples of common serum tumor markers and their associated cancers; their uses in screening (S), diagnosis (D), prognosis (P), and monitoring (M) are also listed.

Laboratory Tests for Tumors

• Immunohistochemistry uses labeled antibodies to detect tumor antigens in tissue biopsies.
• Immunoassays measure circulating tumor marker levels.
• Molecular methods detect genetic mutations associated with cancers. (e.g., PCR, karyotyping, FISH, microarray, DNA sequencing)

Immunotherapy

• Also known as biological response modifier therapy.
• Uses the immune system's ability to destroy tumor cells.
  • Active immunotherapy stimulates patient immune response to tumor antigens—includes preventative vaccines (e.g., HPV, HBV) and therapeutic vaccines (e.g., TSA-specific, Provenge).
  • Passive immunotherapy involves administering soluble components of immune system (e.g., cytokines) to boost immune response and increase white blood cell production; monoclonal antibodies targeting specific tumor antigens also fall under this category.
  • Adoptive immunotherapy involves transferring immune cells to cancer patients (e.g., TILs to melanoma patients or genetically-engineered T cells (CAR-T)).

This quiz covers essential concepts related to tumor markers, their clinical uses, and associations with various cancers, including gestational trophoblastic disease and prostate cancer. Test your knowledge on tumor characteristics, immunological aspects, and molecular alterations in tumor cells.