Tumor Growth and Metastasis

• Chemical carcinogens, irradiation, and certain viruses can alter cell morphology and growth properties, sometimes leading to transformation.
• Malignant transformation via chemical or physical carcinogens includes initiation and promotion steps.
• Initiation involves changes in the genome, without immediate transformation.
• Promotion involves cell division, leading to malignant transformation.

Tumor Growth and Metastasis

• Altered cells proliferate at a specific tissue site, forming a tumor mass.
• Cells become more invasive, spreading to subsequent tissue layers.
• Tumor invasiveness indicates malignancy.
• Malignant tumors metastasize via small clusters of tumor cells dislodging into the bloodstream.
• These clusters travel to other body sites.
• Human cancers linked to viral infections include adult T-cell leukemia (HTLV-1), Kaposi's sarcoma (HHV-8), cervical carcinoma (HPV), and liver carcinoma (HBV).

Immune System Evasion

• Malignant cells can evade both innate and adaptive immune responses by altering the immune system's response, benefiting tumor growth.
• Chronic inflammation, B and T cells in leukemias and lymphomas can contain a pro-oncogene.
• Increased expression of these genes in lymphoid cells increases lymphoma development of the B cell lineage shortly after birth.

Immune Cell Interaction

• Anti-tumor antibodies may mask antigens on tumor cells, inhibiting CTL detection and destruction.
• Antibodies against tumor cells can downregulate the expression of tumor-specific antigens.
• Antigenic modulation decreases tumor antigens temporarily, followed by re-emergence.
• Tumor cells may downregulate MHC class one molecule expression, increasing recognition by NK cells, but decreasing CTL killing.

Tumor Immunity

• Normal cells grow in a controlled manner to form tissues and organs.
• Malignant cells can invade adjacent structures and metastasize.
• Tumors can metastasize when cells break off, enter the bloodstream/lymphatic channels, and travel to other body parts to initiate new tumors.
• Metastasis affects normal tissue function, and is a multi-factorial process with interactions between tumor cells, vessels, basement membranes, and the extracellular matrix.
• The EGFR pathway activates and modulates metastases.
• Signals entering the cell initiate events that lead to the cell nucleus.
• Genes regulating cell cycle progression and cell growth are stimulated.
• Matrix metalloproteinase (MMP) is produced through this activation, and allows tumor cells to break off and enter extracellular space.
• Tumor cells secrete MMP to degrade the extracellular matrix, breaking through the basement membrane.
• This allows tumor cells to migrate toward blood or lymph vessels.
• MMPs break down the vessel's basement membrane for access.
• Tumor cells migrate into the blood and lymph through epithelial cell tight junctions.
• Metastatic tumor cells target some organs, more than others, but the reason why is unclear.
• The migration of tumor cells into organs initially involves weak adhesion to endothelial cells, allowing rolling until stronger bonds form.
• Metastatic cells securely attach to the endothelial lining and enter the tissue, leaving an open pathway for less aggressive tumor cells to invade and grow.

FOXP3 and CD8 T Cells

• A patient with a high number of FOXP3 cells around the neoplastic lesion is likely to have a worse prognosis.
• FOXP3 is a transcription factor expressed in T regulatory cells (Tregs) that suppress immune responses.
• Tregs recruited to tumors inhibit the activity of other immune cells, particularly cytotoxic T cells.
• The presence of a large number of FOXP3 cells indicates immune suppression, which can allow the tumor to evade immune surveillance and grow more aggressively.
• The patient with a large number of CD8+ T cells surrounding the neoplastic lesion is more likely to have a better prognosis since Cytotoxic T cells (CD8+ T cells) are crucial for recognizing and killing tumor cells.
• CD8 T cells directly attack cells expressing abnormal or mutated antigens.
• CD8 T cells indicate the immune system is actively combating the tumor and results in better control over tumor growth.

Cytokines Inhibiting Anti-Tumor Responses and Treatments

• Several cytokines suppress immune responses against tumors, contributing to tumor immune evasion and promoting tumor progression.
• Transforming Growth Factor-beta (TGF-β) is a potent immunosuppressive cytokine produced by tumor cells, tumor-associated macrophages, and regulatory T cells.
• TGF-β inhibits the activation and function of CD8+ T cells, CD4+ T helper cells, and NK cells.
• TGF-β promotes the differentiation and expansion of Tregs, suppressing anti-tumor immunity.
• TGF-β Inhibits cytokine production, suppresses effector T cell functions, and promotes the epithelial-mesenchymal transition (EMT) that enhances metastasis.
• TGF-β inhibitors are being investigated as potential cancer therapies to restore immune responses and improve the effectiveness of checkpoint inhibitors and cytotoxic treatments.
• Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits the activity of T cells and natural killer (NK) cells.
• IL-10 suppresses the production of pro-inflammatory cytokines, limiting the immune response against cancer cells.
• IL-10 also promotes the differentiation of regulatory T cells (Tregs), further suppressing immune activity.
• Immunotherapies targeting IL-10 or its receptors are under investigation.
• Interleukin-13 (IL-13) can modulate the function of immune cells, impairing anti-tumor responses.
• IL-13 targeting strategies are under investigation
• Programmed Death-Ligand 1 (PD-L1): interacts with PD-1 on T cells, leading to T cell exhaustion.
• PD-L1/PD-1 interaction inhibits T cell function, allowing cancer cells to evade immune surveillance.
• Immune checkpoint inhibitors targeting PD-1/PD-L1 are utilized in some cases.
• Classic treatments include Chemotherapy, Radiation Therapy, Immunotherapy and Stem Cell Transplantation.