Malignant Tumors

• A tumor (neoplasm) is defined as unchecked cellular growth, or cellular growth fails to respond to normal regulatory signals.
• There are primarily two types of tumors, benign and malignant.

Malignant Tumors

• Malignant tumors showcase progressive growth without the need for external growth signals.
• These tumors exhibit invasiveness of normal tissue boundaries.
• Malignant tumors can undergo metastasis.
• They are mainly of monoclonal origin.
• These tumors fail to respond to the regulatory signals governing normal growth.

Classification of Malignant Tumors

• Malignant tumors are classified based on their embryonic origin.
• Carcinomas develop from endodermal or ectodermal tissues; examples include skin, colon, and lung carcinomas.
• Sarcomas originate from bone and cartilage.
• Leukemia is a hematopoietic lineage malignant tumor, proliferating as individual cells.
• Lymphoma is a malignant tumor of hematopoietic lineage that grows as a solid mass.

Malignant Transformation

• Malignant transformation involves transforming a normal cellular phenotype into a cancerous one due to genetic mutations in essential cellular genes.
• Mutations responsible for such transformation can be induced by chemical or physical carcinogens, or by oncogenic viruses.
• Rous sarcoma virus-40 can cause sarcoma in tissue culture.
• HTLV (Retrovirus) is associated with adult T-lymphocytic leukemia.
• EBV is linked to lymphoma.
• HPV is associated with cervical carcinoma.

Types of Oncogenes

• Cell division stimulating genes.
• Tumor suppressor genes.
• Regulators of apoptosis.

Cell Division Stimulators

• Cellular oncogene proteins are involved in regulating cell division through the tyrosine phosphorylation pathway (e.g., Src or Abl).
• Cellular oncogene proteins can also act as transcriptional factors for other genes, regulating gene transcription (e.g., fos and Jun).

Tumor Suppressor Genes

• Cellular oncogene proteins inhibit cell division and their mutation leads to loss of function and uncontrolled cell growth.
• P53 when inactivated by HPV can lead to cervical carcinoma.
• Rb acts as a suppressor of retinoblastoma.

Apoptosis Regulators

• Bcl-2 is an anti-apoptotic oncogene found in B-cell follicular lymphoma.
• Bax is a pro-apoptotic oncogene.
• The ratio of Bcl-2 to Bax determines whether a cell survives or undergoes apoptosis.

Types of Tumor Antigens

• Cellular peptides presented by MHC that stimulate a specific T-cell response or are present on the cell surface.
• Tumor-specific Transplantation Antigens (TSTA) are not found on normal somatic cells and are unique to tumor cells.
• Tumor-associated Transplantation Antigens (TATA) are found on normal cells (not unique to tumors), excessively on tumor cells, or expressed on cells where they normally do not exist.

Common Tumor Markers in Blood

• Carcinoembryonic antigen (CEA) is a tumor marker.
• Alpha-fetoprotein (AFP), which is an alpha-globulin, is a tumor marker.
• HER2/neu is increased in breast cancer.
• Prostatic specific antigen (PSA) is a tumor marker.

Immune Surveillance

• Innate immunity involves the role of Natural Killer (NK) cells in tumor killing.
• Macrophage cytokines such as TNF-α and TNF-β stimulate tumor necrosis.
• TNF-α inhibits angiogenesis and the growth of new vessels.
• INF-α and INF-β up-regulate MHC I expression.
• Activated lymphocyte cytokines, such as INF-γ, directly inhibit tumor proliferation.

Adaptive Immunity

• Antibodies and humoral responses: ADCC is mediated by NK cells, complement activation leads to cell lysis, and opsonization enhances the phagocytosis of tumor cells.
• CTL effect involves direct cytotoxicity on tumor cells by effector CD8 cells using perforin and granzyme.
• DTH effect is mediated by the effector CD4 function.

Tumor Escape Mechanism

• Tumors evade immune recognition by not expressing neo-antigens or co-stimulatory molecules required for the T-cytotoxic response.
• Tumors also evade recognition by not expressing MHC-I on their surface.
• Rapid proliferation aids tumors in escaping immune detection.
• Production of immunosuppressive molecules that activate T-regulatory cells.
• Shedding of their antigens in plasma.
• By covering their mass using plasma proteins and antibodies.

Immuno-diagnosis

• Monoclonal antibodies labeled with radioisotopes are used for in vivo detection of small tumor foci.
• Antibodies labeled with fluorescent dyes are used in vitro for staining tissue biopsies to confirm suspected diagnoses.

Immunotherapy

• Anti-Her2/Neu antibodies treat breast cancer.
• Anti-IL-2R antibodies are used for treating adult T-cell leukemia.
• Anti-CD20 antibodies are used for non-Hodgkin's lymphoma.
• Antibodies conjugated with toxin (Pseudomonas toxins) or anticancer drugs can be used therapeutically.

Problems in Passive Therapy

• Antibodies may not bind to the MHC-I-epitope complex.
• Serum sickness can occur due to tumor antigens.

Non-Specific Immunotherapy

• Transfer of tumor-infiltrating lymphocytes after IL-2 activation from in vitro culture.
• Transfer of dendritic cells activated by tumor antigen in tissue culture can cause a specific Tc response against the tumor.
• IL-2 is used in the treatment of renal cell carcinoma.
• INF-Gamma is used in the treatment of ovarian cancers.