Module 3.8 Cancer Biology

Cancer

diseases in which abnormal cells divide without control and can invade other tissues, a major cause of illness and death; has an environment, hereditary, and behavioral component

Benign tumors

grow slowly, encapsulated, non-invasive, well differentiated, low mitotic index, do not metastasize

Malignant tumors

grow rapidly, not encapsulated, invasive, poorly differentiated, high mitotic index, can metastasize

Cancer classification

cancers are classified by their cell origins

Sarcoma

cancer that originated in connective tissue

Lymphoma

cancer that originated in lymphatic tissue

Leukemia

cancer that originated in blood forming cells

Melanoma

cancer that originated in pigment-producing cells

Adenocarcinoma

cancer that originated in glandular epithelial tissue

Carcinoma in situ

early stage cancers; pre-invasive epithelial tumors of glandular or squamous cell origin, have not broken through the basement membrane or invaded the surrounding stroma

Carcinoma in situ outcomes

remain stable, progress to invasive and metastatic cancers, or regress and disappear

Two fundamental concepts to the biology of cancer

cancer is a complex disease and the tumor microenvironment is a heterogenous mixture of cells, both cancerous and benign

Stages of cancer development

tumor initiation, tumor promotion, and tumor progression

Tumor initiation

triggering event, genetic alterations(proto-oncogenes, tumor suppressor genes, DNA repair genes), clonal origin, cell is not malignant yet

Tumor promotion

increased cell proliferation, inhibition of apoptosis, chronic inflammation, altered gene expression, disruption of cell-to-cell communication

Tumor progression

irreversible and aggressive, genetic instability, increased invasion and metastasis, angiogenesis, escape from immune destruction

Anaplasia

a loss of cellular differentiation, resulting in cancer cells that appear more primitive and less specialized

Cancer cell surface changes

enables tumor progression; can be decreased cell-to-cell adhesion, altered glycans(immune evasion, signaling dysregulation, metastasis), altered receptors and antigens, changes in surface charges, changes in cell-ECM communications

Familial cancer syndromes

mutations in certain genes that are passed down from parent to child

Signs of hereditary cancers in families

cancer occurring at younger than average age, multiple family members with the same type of cancer, and cancer occurring in sex not typically affected

Hereditary breast and ovarian cancer(HBOC) syndrome

commonly caused by mutations in the BRCA1 and BRCA2 gene, significantly higher risk of breast and ovarian cancer, also increased risk of pancreatic and prostate cancer and melanoma, an autosomal dominant pattern

Cancer stem cells(CSC)

resistant to standard chemotherapy, responsible for reoccurrence

Stem cell theory of cancer

rare sub-population, driving tumor growth, therapy resistant, cancer reoccurrence, metastasis and progression

Chronic inflammation & cancer

an important factor in the development of cancer, some organs are more susceptible to oncogenic effects of inflammation, successful tumors can alter inflammation to benefit their growth

Helicobacter pylori

chronic inflammation associated with peptic ulcer disease, stomach carcinoma, and mucosa-associated lymphoid tissue lymphomas

Bacterial and viral causes of cancer

bacterial and viral infections can cause cancers by inducing chronic inflammation, disrupting cell cycle control through genetic mutations, and weakening the hosts immune system

Bacterial and Viral infections that cause cancer

Hep B&C(hepatocellular carcinoma); HPV- 16, 18, 31, 45(cervical, anogenital, penile cancer); Epstein-Barr virus(B-cell non-Hodgkin lymphoma, Burkitt lymphoma, nasopharyngeal carcinoma), HIV-1(non-hodgkin lymphoma, squamous cell carcinoma, Kaposi sarcoma)

Metastasis

the spread of cancer cells from the original tumor site to distant tissues and organs

Metastatic cascade

local invasion, intravasation, circulation, extravasation, metastatic colonization

Local invasion

detachment of cancer cells from the primary tumor, invasion of nearby tissues, and breaking through the basement membrane of their primary tumor

Intravasation

cancer cells enter the blood vessels or lymphatic system, traveling through the circulatory or lymphatic systems

Circulation

cancer cells move through blood stream or lymphatic system, surviving against the immune system and physical stresses

Extravasation

cancer cells exit the blood vessels or lymphatic system at distant sites, adhering to and penetrating the walls of new tissue

Metastatic colonization

cancer cells establish a secondary tumor in a new tissue of origin, adapting to the new environment and proliferating to form a metastatic lesion

Factors implicated in tumor metastasis

rate of growth, angiogenesis, lack of cellular adhesion, absence of cellular barriers

Growth rate implications on metastasis

increased detachment and spread, correlations with poor outcomes, different growth patterns, influence on treatment

Angiogenesis

provides both a physical route for cancer cells to enter bloodstream and supplies nutrients in tumors; provides pathway for intravasation, increases vascular permeability, promotes degredation of vessel walls, enables growth and development, and facilitates extravasation

How lack of cellular adhesion is implicated in tumor metastasis

detachment from primary tumor, increased motility, spread through circulation and colonizing new sites, and epithelial to messenchymal transition(cadherin switching)

How absence of cellular barriers are implicated in tumor metastasis

epithelial to messenchymal transition(cadherin switching), breakdown at basement membrane, and breakdown of cellular matrix

Clinical manifestations of cancer

dependent on the type of cancer, staging, and individual patient

Common(and vague) cancer signs and symptoms

fatigue, unexplained weight loss, fever, night sweats, bruising easily

Paraneoplastic syndrome

symptom complexes triggered by a cancer but not caused by tumor mass

Cachexia

a metabolic disorder and the most severe form of malnutrition; caused by tumor related factors, cancer treatments, inflammation, nutritional deficiencies, and psychological factors

Cancer discovery

after screening tests, routine examinations, and symptom investigation

Tumor tissue samples

can be a excisional biopsy, incisional biopsy, core needle biopsy, fine-needle aspiration, exfoliative cytology, or liquid biopsy

Tumor markers

detect cancer at early stage, monitor cancer progression, assess treatment effectiveness, identify recurrence, and not used alone for definitive diagnosis

Common ones: PSA, CEA, AFP, hCG, and CA-125

PSA tumor marker

prostate-specific antigen, for prostate cancer

CEA tumor marker

carcinoembryonic antigen, for colon and rectal cancer

AFP tumor marker

alpha-fetoprotein, for liver cancer

hCG tumor marker

human choreographic gonotropin, for testicular and ovarian cancer, can also be used to diagnose a pregnancy

CA-125 tumor marker

for breast cancer

Tumor staging

a system to describe the size, location, and extent of a cancer; TNM system used where T indicates tumor spread(1-4), N indicates node involvement(X-3), and M indicates the presence of distant metastasis(X-1)

Importance of staging

treatment planning, prognosis, and clinical trials

Cancer treatment strategies

the goal is to destroy or control the cancer cells while minimizing harm to the healthy tissues; can be by surgery, chemotherapy, radiation, or immunotherapy

Surgery

may be definitive if cancer has not spread beyond limits of surgical excision, clean margins are important, can be palliative or preventative

Chemotherapy

nonselective cytotoxic drugs, targets any rapidly dividing cell, single agent or combination chemotherapy, goal is to eliminate enough tumor cells so the body’s defense can eradicate any remaining cells

Neoadjuvant chemotherapy

administered to a patient before surgery to help shrink a tumor or stop disease spread

Adjuvant chemotherapy

administered after surgery to kill any remaining cancer cells in the area and lower the risk of reoccurrence

Radiation

ideal for localized disease that are difficult to reach surgically, can be an external beam or brachytherapy(radioactive seeds)

External beam radiation

most common and causes molecular DNA damage; can be lethal, potentially lethal, and sublethal; more effective with strong local delivery of oxygen; also causes irreversible damage to normal cells

Immunotherapy

utilizing patients own immune system to recognize and destroy cancer cells; can be done through immune checkpoint inhibitors, adaptive cell transfer, monoclonal antibodies, oncotic virus therapy, cancer vaccines, and immunomodulators

Immune checkpoint inhibitors

drugs that block the proteins that cancer cells use to hide from the immune system allowing T-cells to be more effective

Adaptive cell trasnfer(ACT)

involves re-engineering the patients own immune cells

Monoclonal antibodies

more common, custom made proteins designed to attach to specific target antigens on cancer cells, can be used to disrupt cancer cells

Oncotic virus therapy

natural or genetically modified viruses to infect and kill the cancer while stimulating the immune system to fight the cancer

Cancer vaccines

can be therapeutic or prophylactic(more common)

Immunomodulators

substances that change the way the immune system responds to cancer

Cancer treatment common side effects

fatigue, hair loss, appetite changes, nausea and vomiting, skin and nail changes, taste changes

Less common cancer treatment side effects

anemia, thrombocytopenia, leukopenia, bowel and bladder issues, cognitive changes, pain, neuropathy, lymphedema, emotional and psychological effects