Viruses and Cancer

• 20% of all cancers are caused by viruses
• Viruses can integrate into the host genetically or cause mutations in the host epigenetically

Transformed Cells

• A virus takes up residence in a cell and alters its biological properties

Environmental Factors Causing Cancer

• Inherent characteristics
• Built environment (epigenetics)
• Natural environment (influenced by humans)
• Behavioral contributions
• Social environment
• Policies/programs

Papillomavirus (HPV)

• Can cause penile, anal, vaginal, uterine, and cervical carcinomas (epithelial)
• Circular, capsid, DNA cancer accounts for 16% of female cancers and 10% of all cancers
• 170 types of HPV infect humans, 18 are high risk for cancer
• Transmitted through tiny breaks in the skin or mucous membranes, usually sexually or perinatally
• Laryngeal papillomatosis is oropharyngeal cancer caused by oral HPV infection, more severe in children
• Genital warts occur in areas of skin infected with HPV 6/11
• Warts consist of keratinized epithelial tissue that has normal KI67 expression and no loss of control
• Warts can convert to carcinomas of the skin, esophagus, larynx, and lung

Harald zur Hausen (1936)

• Discovered that papillomavirus (HPV 16/18) causes cervical cancer
• Research led to a vaccine in 2006 and a Nobel Prize in 2008

Papillomavirus Vaccines

• Gardasil (Merck): 3 doses over 6 months, protects against HPV types 6, 11 (warts), 16, and 18 (cancer), and offers 5 years of protection
• Cervarix (GlaxoSmithKline): 3 doses over 6 months, protects only against HPV types 16 and 18, and offers 7.4 years of protection

Cervical Cancer

• 270,000 women die from it each year
• Almost all cases are directly caused by HPV 16 and 18
• Can also be indirectly caused by HSV-2 (smoking/genital infections), which stays dormant in the brain until there is trauma to the head

Cervical Cancer Stages

• Early stage 1B usually has no symptoms and is contained within the cervix
• Late stage 1B has spread beyond the cervix but hasn't reached anything else
• Stage 2B

Retroviruses

• Transmitted sexually, through breastfeeding, and through blood transfusions
• Viral infection in a proto-oncogene leads to reverse transcriptase converting ssRNA to dsDNA
• dsDNA integrates into genomic DNA and is coded into an oncogene
• Blocking reverse transcriptase can prevent cancer development

HTLV (Human T-lymphotropic virus)

• Targets CD4+ T lymphocytes, leading to adult T-cell leukemia
• Sexually and parenterally transmitted
• HTLV-1 multiplies cells via Tax and causes rosettes (clumps)
• Asymptomatic period of 20-40 years

Proviruses

• Proviruses can become integrated into host DNA, leading to cancer
• Activating an adjacent proto-oncogene, requiring rearrangements
• Carrying a captured proto-oncogene due to mistakes during replication
• A provirus-coded protein activates cellular genes, carrying an activator that immediately activates

DNA Viruses

• Cause fast cancer development through two mechanisms
• Viral DNA carrying an oncogene is brought to the DNA and waits to be activated
• Viral DNA activates a proto-oncogene by integrating next to it, causing it to become overactive and become an oncogene
• Some people are predisposed to have more of these proto-oncogenes

Viral Induced Inflammation

• Cells divide quickly when under stress, which leaves more room for mistakes and stimulates tumor/blood vessel growth
• This leads to genetic instability
• Suppressing inflammation can reduce viral proteins
• HCV (HepC): Flaviviridae, causes chronic liver inflammation, and hepatocellular carcinoma develops in 50% of cases over 10 to 30 years
• HBV (HepB): Chronic hepatitis leads to hepatocellular carcinoma in 25% of cases
• Possible mechanisms of hepatitis B virus involvement in oncogenesis:
  • Integration of viral DNA induces synthesis of HBxAg, which binds to p53
  • Repression of the beta-interferon promoter
  • Integration within a cell cycle control gene, cyclin
  • Integration near a hormone response gene, altering control
  • Deletion of the anti-oncogene p53

Epstein Barr Virus (EBV)

• Herpesvirus where epigenetics plays a role in response to infection
• Burkitt's lymphoma in Africa with jaw and face tumors overlapping with malaria, possibly due to genetic association
• Nasopharyngeal cancer in China
• Tumor of the epithelium of the upper respiratory tract
• Results in genetic and environmental predisposition

B cell lymphoma

• Occurs in people with weakened immune systems
• EBV-infected B cells have a higher opportunity to proliferate

Hairy leukoplakia

• Occurs in people with advanced weakened immune systems (bad HIV)
• Characterized by a high density of white papillae on the tongue

HHV 8

• Transmitted through saliva, organ transplantation, and blood transfusion
• Kaposi's sarcoma presents with cutaneous purple lesions (macular, patch, plaque, nodular)
• AIDS-related KS lesions affect the upper trunk, face, and oral cavity

Clinical Aspects of Cancer Treatment

• Cancer treatment main concerns include delivery efficacy, sustained delivery, stability, bioavailability, pharmacological activity, and feasibility of various delivery routes of administration

Biomarkers

• Physiological (blood pressure, temperature, breath sound), molecular (RBC count, cholesterol levels), and imaging (tumor mass, bone fractures) indicators

Biomarker Types

• Susceptibility: Prior to cancer (e.g., blood/saliva sample to test for BRCA1/2)
• Diagnosis: After disease establishment
  • Sensitivity: Ability to produce a positive test 100% of the time when positive
  • Specificity: Ability to produce a negative test 100% of the time when negative
  • MART overexpression in melanoma
• Monitoring: Repeated measurements assess disease progression (changes in cancer state)
  • E.g., PSA levels (high = cancer)
• Prognostic: Assess the current state to predict progression
  • E.g., TMN system, Gleason score
• Predictive: Predict which therapy will have the best response
  • E.g., HER2-positive breast cancer = more responsive to trastuzumab
• Responsive: Reflects treatment efficacy (how quick)
  • E.g., tumor size
• Safety: Monitors adverse effects as a result of treatment
  • An indicator of a potential need to change therapies

Classical Cancer Treatments

• Only option (3000 BC evidence) involves surgery for a long time
• 1900: Marie Curie discovered radiation
  • Can damage the DNA of cancer cells, stopping them from growing and dividing
• 1940: Chemotherapy
  • Targets the entire body instead of being localized to a tumor
  • Side effects are too severe and attacks any rapidly dividing cell, healthy or not
  • Knowledge was essential for future discoveries
• 1980: Targeted therapy (MAB)
  • Uses monoclonal antibodies and inhibitors to inhibit the growth signals of specifically cancer cells or flag them for destruction
  • Targets specific molecular pathways

2000-2020 Cancer Treatments

• Hormone Therapy: Blocks or downregulates hormone production
  • Corticosteroid hormones, in combination with chemo, manage side effects and make cells more sensitive
  • Sex hormones for reproductive system cancers
  • Anastrozole cuts levels of estrogen women produce, blocking enzyme aromatase
• Ablation Therapy: Destroys solid tumors using radio-frequencies/microwaves or cryoablation
  • Used for tumors <3 cm (not near major blood vessels, diaphragm, major bile ducts)
• Stem Cell Therapy: Transplants healthy stem cells into chemo patients' bodies to replace damaged cells
  • Long recovery period needed
  • Sources include bone marrow, peripheral blood, blood cells, and hematopoietic stem cells
• Immunotherapy: Uses the body's own defenses to target cancer, making the tumor more recognizable to the immune system
  • Blocks tumor-specific genetic alterations and T-cell inhibitors

Immunotherapy Types

• Cellular: Transfers healthy cells into the body to replace diseased ones
  • Car-T cell therapy for lymphomas and leukemias involves genetically engineering a patient's T cells to express a CR, then reinfusing them into the blood, can lead to cytokine release syndrome
• Immunomodulators: Regulate immune response through medications like checkpoint inhibitors and cytokines. Discovery of checkpoint inhibitors contributed to immunotherapy
• Oncolytic Virus Therapy: Lab-modified viruses make the body develop antibodies
• Monoclonal Antibodies: Lab-made proteins attack part of the cancer cell
• Vaccines: Trains immune system to kill cancer cells. By 2027, 200 patients will be given up to 15 doses of personalized vaccines

Immunotherapies Work Properly

• Dendritic cells
• Complement: Creates holes so things can go in/out, which makes cells burst
• Neutrophils
• Transforming growth Macrophages factor beta (TGFβ)
• NK cells release perforin and granzyme-containing granules, which causes apoptosis
• Cytokines (interleukins; IL-10, IL-12); cancer identification (cancer wants to minimize expression of these)
• T cells
  • Recognize tumor antigens and produce antibodies in response
  • Antibodies induce arrest of tumor growth or mediate antibody-dependent cellular toxicity by arming effector cells
  • B cells
• Coordinated tumor immunity through immune-mediated rejection of established Her-2 positive breast tumors

Tumor Ecosystem

• Cells talk to each other through signals, growth factors, and direct contact
• Stromal cells (modified tissue cells) provide structural support
• Vascular, endothelial, and pericytes physically block blood cell pores
• Ways to get into blood vessel:
  • Lipid-soluble substances: Diffusion through membrane
  • Water-soluble substances: Movement through intercellular clefts
  • Water-soluble substances: Movement through fenestrations
  • Large substances: Transport via vesicles or caveolae
• Inflammatory cells:
  • Tumor-associated macrophages: Release VEGF and enzymes that remodel the extracellular matrix
  • Mast cells: Release histamine, which makes blood vessels more permeable
• Immune cells: Includes growth factors (VEGF) and chemokines (IL6/8): attract inflammatory cells
• Collagen (protein):
  • Fibrosis: Buildup of collagen keeps the angiogenic switch stuck in the ON position

Tumor Microenvironment

• Includes 2 outcomes of interactions between tumor cells and immune cells:
  • Cytokines secreted by tumor and immune cells promote overall tumor development and tumor cell survival
  • Cytokines secreted by tumor and immune cells exert antitumor effects
• IL-10 is most common, where suppressed = antitumor immunity

Hallmarks of Cancer

• Sustained proliferation comes from a mutation in an oncogene, resulting in altered autocrine signaling
• Evading growth suppressors occurs as a result of loss of function mutation in a tumor suppressor gene, or methylation/mutation of cell cycle checkpoint genes
• Resisting apoptosis occurs via overexpression of anti-apoptotic genes, loss of function of pro-apoptotic genes, or dysregulation of death receptor pathways
• Replicative mortality comes from bypassing the limited replicative lifespan of normal cells via reactivation of telomerase
• Activating invasion and metastasis allows it to invade neighboring healthy tissue and spread to distant organs through the blood/lymphatic system via loss of cell adhesion molecule
• Inducing angiogenesis forms blood vessels that are precocious, convoluted, excessively branching, distorted, and enlarged, erratic blood flow, microhemorrhaging, and abnormal levels of endothelial proliferation and apoptosis
• Angiogenesis needs 1 million cells (400um) in order, oxygen diffusion limit
• Process involves releasing pro-angiogenic factors (VEGF), which diffuse into surrounding tissue and bind to nearby endothelial cells
• Angiogenic inhibitors should be be refractory

Cancer Genes Types

• Proto-oncogenes
  • Normal is positive regulator
  • Mutated to gain of function
• Oncogenes
  • Normal aid cell division and or survival
  • Mutation changes gene expression that is excessive + uncontrolled cell division
• Tumour suppressor genes (anti-oncogenes)
  • Normal negative regulator
  • Mutation loss of function that inhibits cell division and reduces apoptosis
• DNA repair genes
  • Normal recognition and removal of DNA lesions
  • Mutation genome instability that increases the risk of cancer development