Unit 2: Carcinogens, Tumor Immunity, and Laboratory Diagnosis

Sir Percivall Pott

- connected chimney sweeps soot exposure and lack of cleaning to increased risk for scrotal cancer

types of carcinogens

- chemical

- radiation

- oncogenic DNA viruses

- oncogenic RNA viruses

- oncogenic bacteria

carcinogen

- any agent that causes damage to the DNA or inhibits or damages the DNA repair mechanism

environmental carcinogens examples

- natural and man made chemicals

- radiation

- viruses

- bacteria

chemical carinogens

- mutagenic (can cause mutations)

- DNA, RNA, proteins are the targets and cause NON-LETHAL cell damage

examples of chemical carcinogens

- asbestos

- arsenic

- nickel

- chromium

- insecticides

- fungicides

- formaldehyde

- tobacco smoke

- etc...

aflotoxin B1

- from mold Aspergillus

- grows in improperly stored grains and nuts

- incidence of hepatocellular carcinoma related to storage pattern

- usually seen in Africa and far east, high incidence with mutation of codon 249 of p53

radiation

- UV rays and ionizing radiation

- damage takes a long time to be observed

- UV radiation may lead to increased risk for skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma)

sun burns

- overwhelm nucleotide excision repair pathway causing mutation rate to increase

ionizing radiation example

- Hiroshima and Nagasaki

- increase in leukemias after 7 years (CML, AML)

- later many solid tumors (longer latent period)

HPV

- human papillomavirus

- extremely common

- infects host epithelial cells through tiny cuts or breaks

- greater than 30 strains of HPV infect humans

low risk HPV strains

- include 1, 2, 4, 7 which cause benign squamous papillomas (warts)

- include 6 and 11 which can cause genital warts

high risk HPV strains

- include 16 and 18

- cause cervical cancer (80%) as well as others (anal and vaginal cancer)

- accounts for 2/3 of all cervical cancer cases worldwide

HPV causing cancer

- oncogenic DNA virus

- viruses expresses E6 and E7

- E6 prevents p53 from inducing apoptosis

- E7 binds to Rb and prevents it from stopping growth of damaged cells

HPV vaccine

- two vaccines (Gardasil and Cervarix)

- recommended for girls 11-26

- recommended for boys and men age 13-21

hepatitis viruses (HAV and HCV)

- oncogenic RNA viruses

- about 4.4 million Americans live with chronic hepatitis

- can remain clinically silent with chronic infection

- increased risk for liver disease and cancer

- common reason for liver transplantation

Helicobacter pylori

- oncogenic bacteria

- responsible for most ulcers and chronic gastritis

-chronic gastritis can lead to gastric atrophy, dysplasia, and cancer

- coffee, smoking, and alcohol use increase the risk of developing an ulcer for H. pylori

chronic gastritis increases risk for ...

- gastric cancer

- gastric mucosa-associated lymphoid tissue (MALT) lymphomas

- stomach cancers

tumor immunity

- the idea that tumor cells are not entirely self and may be recognized by the immune system

- ex: tyrosinase & cancer/testis antigen (found more in cancer cells than in regular cells)

evidence for immune reactivity of tumors and immunoserveillance

- infiltration of tumors with mononuclear cells (lymphocytes and monocytes) results in better prognosis

- surgical removal of primary tumor causes decrease in metastasis

- immune compromised patients and tumor incidence

- tumor incidence in young and old

- tumor antigen immunization

- tumor specific antibodies and T cells (CAR-T therapy)

example of immune therapy

- PD-1 and PD-L1 block

- tumor expresses PD-L1 which binds to PD-1 to stop T cells from attacking

- blocking this may help activate T cells (ex: nivolumab)

cachexia

- side effect of involvement of immune system

- TNF released from macrophages leads to fat mobilization, suppression of appetite

- progressive loss of body fat and lean body mass

- weakness, anorexia, anemia

- no treatment options yet

- weakness limits chemotherapy dosing

- 20-30% of cancer deaths are attributed to cachexia

ways to get a tumor sample

- excision/biopsy

- needle aspiration

- cytologic smears (pap smear)

- bone marrow

- body fluids/blood

- frozen section (quick view as patient is operated on to check margin)

- imperative sample is stored properly at 4 degrees C

ways to analyze tumor sample

- histology and cytology

- immunohistochemistry

- flow cytometry (for non-tissue bound cells, like blood cancer)

- molecular diagnostics

histology and cytology

- H+E stain

- colors structures in various shades of red, pink, and orange

immunohistochemistry

- antibody staining of tissue

treatment types

- surgery

- chemotherapy

- radiation therapy usually in conjunction with chemotherapy

- immunotherapy

- anti-angiogenesis treatment (ex: anti-VEGF mab)

- hematopoietic stem cell transplant

- laser in cancer treatment

- molecular targeted therapy