NEOPLASMS - MODULE 3

What two processes must occur for normal renewal in cells to take place?

1. cell proliferation: rapid division replacing old cells

2. cell differentiation of cells

How does neoplasia occur?

• loss of either cell proliferation, cell differentiation, or both

What is a benign tumor?

• lost ability to control proliferation

  • growth is slow and may stop

  • made of well differentiated cells + well organized stroma

  • dont invade beyond their capsule

  • no metastasis

• named with suffix oma (e.g. lipoma, benign tumour of fat cells

When do benign tumors become a problem?

• if growth interferes with function of surrounding tissue

• e.g. compression of brain tissue or inappropriate hormone production

What is a malignant tumor?

• rapid growth rate

• anaplasia

• loss of tissue organization

• pleomorphic cells

• lacks a capsule and can invade nearby blood vessels, lymphatics, and surrounding structures

• ability to metastasize

• referred to as cancer

What is anaplasia?

• loss of cell differentiation

What are pleomorphic cells?

• cells in different sizes and shapes

How are malignant tumors named?

• origin cell type

• carcinoma = epithelial tissue

• sarcoma = mesenchymal tissue (connective, bone, muscle)

  • e.g. adenocarcinomas from glandular tissue

What are examples of specialized names of malignant tumors?

• lymphomas are lymphatic tissue

• leukemias are cancers of blood forming cells

What are the two categories of malignant tumors?

• solid (only in specific tissue / organ)

• hematologic (found in blood / lymph)

What is the concept of carcinoma in situ?

• cancer in its place

• growth with malignant characteristics in epithelial tissue

  • no local tissue invasion yet

  • pre cancerous

• difficult to deal with

• can remain stable, become malignant, or regress

• occurs in berast, cervix, skin, stomach

What are the 8 cancer cell characteristics?

1. genetic instability

2. independence of external growth signals

3. loss of contact inhibition

4. decrease in cell adhesion

5. loss of anchorage dependence

6. production of unusual antigens

7. division without limit

8. altered metabolism

What is the genetic instability characteristic in cancer?

• high mutation frequency in cancer cells

  • e.g. deletions / insertions / substitutions of bases, loss / gain of chromosomes

• normal cells have mechanisms to correct mutations

What is the independence of external growth signals in cancer cells?

• can make their own

• don’t need any (e.g. breast cancer cells)

• extremely sensitive to growth factors

  • e.g. a type of breast cancer has more receptors on cell surface so response is increased

What is the loss of contact inhibition characteristic in cancer?

• cancer cells pile up on each other

  • normal cells stop growth after contact

What is the decrease in cell adhesion characteristic in cancer?

• cancer cells have less cadherin

  • easily shed from tumors

  • increases mestasis possibility

What is cadherin?

• membrane structure on normal cells that allow them to stick together

  • less amount in cancer cells

What is the loss of anchorage dependence characteristic in cancer cells?

• cancer cells survive and grow in conditions that normal cells cant

  • may help metastasis

  • normal cells die if not attached to underlying extracellular matrix

What is the production of unusual antigen characteristic of cancer cells?

• cell surface markers, enzymes, or hormones that are not made by origin tissue

  • e.g. cancer antigen 15-3, carcinoembryonic antigen

  • e.g. ACTH, parathyroid hormone

What is the ability to divide without limit characteristic of cancer cells?

• normal cells have telomeres; if short enough, cell doese not divide anymore

• cancer cells have telomerase that lengthens telomeres, allowing unlimited division

What is the altered metabolism characteristic of cancer cells?

• cancer cells are hungry and greedy

• cancer cells mainly use anaerobic respiration (glycolysis)

• yields much less ATP

• uses much more glucose than regular cells

How can the altered metabolism characteristic of cancer cells be used for detection?

• a fluorescent compound can be taken up by cells in the same way as glucose

  • cannot be metabolized

  • accumulates in cells that would take up lots of glucose

What is metastasis?

• definining cancer characteristic

• the spread of cancer to distant organs and tissues

• more challenging to treat

  • non metastasized cancer is easier to cure with surgery, chemotherapy, and / or radiation

What is the local spread mechanism of metastasis?

• helped by enzymes from cancer cells

  • breaks down cells and connective tissue of surroudnings

• growth is via crablike extensions sent into surrounding tissue

What is the distant spread mechanism of metastasis?

• cancer cells must be able to invade lymph and blood vessels

  • helped by lymphangiogenesis and neoangiogenesis

  • carcinomas spread in lymph

  • sarcomas spread in blood

What happens if cancer spreads through the lymph?

• tumor cells lodge in the sentinel node (inital drainage node)

• examination of sentinel nodes can show if metastasis has occurred

What happens if cancer is spread through the blood?

• the organ that is next in the vascular pathway may most likely be affected

  • (e.g. the liver is common for metastasis from intestines)

• can be an organ that supplies a similar environment as the original tumor tissue

  • (e.g. same growth factor type)

What is the entire process of invasion and metastasis in cancer cells?

1. must evolve characteristics needed to metastasize

2. initially invade the interstitial spaces of local tissue

3. if carried by lymph drainage, it goes to sentinel lymph nodes

4. enter venous system as lymph drains into subclavian veins

5. must evade innate immunity by mimicking normal cells (e.g. coating with platelets)

6. secrete proteolytic enzymes to penetrate tissues from blood vessels (vice versa)

7. release cytokines + growth factors to control invaded tissue function

Why do tumor cells need to release cytokines and growth factors once seeded?

• to control invaded tissue function

  • to stimulate growth and proliferation

  • cancer must develop angiogenesis ability if it grows more than 1mm in diameter

What are the 6 local effects of tumors?

1. compression

2. obstruction

3. hemorrhage

4. infarction

5. rupture / perforation

6. effusions

What is the local effect of compression?

• e.g. brain tumor

  • headaches, nausea, loss of conciousness, death

  • local nerve compression = loss of function and sensation

What is the local effect of obstruction?

• e.g. blockage to airways or gut

What is the local effect of hemorrhage?

• damage to blood vessels

  • e.g. intestine and lungs

What is the local effect of infarction?

• mass growth

  • obstructs blood vessels

  • causes local necrosis of tissue (ulceration and bleeding)

  • e.g. blood in stool from colorectal cancer

What is the local effect of rupture or perforation?

• affects gut and ovary

What is the local effect of effusions?

• inappropriate amounts of fluid

  • in pleural, pericardial. or peritoneal space

• up to 65% of women with ovarian cancer present with ascites

  • excess fluid in peritoneal cavity

How do effects relate to symptoms?

• effects are usually combined + relate to symptoms

  • e.g. lung cancer may present with chest pain, shortness of breath, cough, wheezing, and blood in sputum

What are the 8 systemic manifestations of cancer?

1. paraneoplastic syndrome

2. pain

3. fatigue

4. cachexia

5. anemia, leukocytopenia, and thrombocytopenia

6. infection

7. GI tract issues

8. hair and skin issues

What is the systemic manifestation of paraneoplastic syndrome?

• symptoms triggered by substances released by cancer cells

  • not caused by direct local effects of the tumor mass

  • some tumors release hormones that may have systemic effects

    • e.g. small cell carcinoma of the lung releases an ACTH like substance

      • causes cushing syndrome

What is the systemic manifestation of pain?

• strong in later stages

• little or none in early stages

• can result from pressure, obstruction, and inflammation

• important to control rapidly and completely

What is the systemic manifesation of fatigue?

• not relieved by sleep or stress

• due to sleep disturbances, biochemical changes, nutritional status, etc

What is the systemic manifestation of cachexia?

• loss of body mass due to metabolic disturbances caused by a disease

  • cannot be reversed nutritionally

• caused by altered metabolism leading to inefficient energy use

• compounded by side effects of cancer / treatment

  • depression, anorexia, loss of taste, early satiety (fullness)

What is the systemic manifestation of anemia, leukocytopenia, and thrombocytopenia?

• caused by chemotherapy, radiation, and malignancy in blood forming organs

  • anemia is also caused by chronic bleeding and malnutrition

What is the systemic manifestation of infection?

• most significant cause of complications and death '

  • due to loss of immune cells

• increased risk from surgery, poor tissue perfusion, and indwelling devices (e.g. catheters)

What is the systemic manifestation of GI tract issues?

• chemotherapy and radiation therapy affects epithelial lining causing

  • oral ulcers

  • malnutrition

  • nausea

  • infection

What is the systemic manifestation of hair and skin issues?

• alopecia

• skin sensitivity, pain, burns due to rapidly growing tissue being affected by therapies

What is carcinogenesis?

• small number of changes in the cell’s genetic material

  • allows cells to divide with less inhibition

  • causes more division

• cancer rate increases with age due to accumulation of mutations over a lifetime

What are proto-oncogenes?

• genes that code for proteins that cause cell division

  • happens in their normal state

  • e.g. growth factor, GF receptors, or proteins involved in transmitting signals

What happens when proto-oncogenes mutate?

• called oncogenes

• cells divide uncontrollably

  • e.g. RAS family of proteins that transmit the growth signal from the membrane receptor to the nucleus

    • (involved in 30% all cancers)

What are anti-oncogenes?

• genes that code for proteins that slow cell division rate / stop it when cell is damaged

• if one gene copy is inactivated, the other will still function

• these are the genes involved in cancer that can be inherited

  • e.g. BRCA1 gene in breast cancer, p53 gene (guardian of genome, inactivated in > 50% cancers)

How do changes in metabolic pathways inside cells contribute to cancer development?

• loss of DNA repair machinery that could fix an oncogene

• loss of apoptosis ability

How do changes in the control mechanisms for gene expressions contribute to cancer development?

• may have normal tumour supressor genes

  • may not be active

What are epigenetics?

• DNa sequence remains the same but genes can be switched on / off

• epigenetics is impacted by lifestyle

  • e.g. stress, diet, exercise

What are the 3 steps to carcinogenesis?

1. initiation

2. promotion

3. progression

What is the initiation step of carcinogenesis?

• exposure to carcinogenic agent

• irreversible mutations to genome

• cells in mitosis or meiosis are most susceptible

What is the promotion step of carcinogenesis?

• cytokines and growth factors begin cell proliferation

What is the progression step of carcinogenesis?

• tumour cells eventually acquire all the characteristics needed for:

  • invasion

  • metastasis

What role does inflammation play in cancer etiology?

• chronic inflammation is an important cancer development factor

• inflammation and cancer both involve:

  • migration of neutrophils, lymphocytes, and macrophages + the release of factors that stimulate cell and blood vessel growth

  • release of compounds that promotes mutations (e.g. ROS)

What role do viruses play in cancer etiology?

• viruses ahve been associate with cancer from virus changing cell DNA or inflammation

• up to 80% of liver cancer cases are associated with chronic hepatitis

• all cervical cancer is caused by infections with specific HPV subtypes

  • viral DNA integrates in host DNA and activates proto oncogenes

• EBV / infectious mononucleosis infects B cells and stimulates growth

  • may lead to B cell lymphomas if person is immunosuppressed

What role does bacteria play in cancer etiology?

• chronic infection with helicobacter pylori and inflammation are linked to gastric carcinoma

• factors on top of the initial infection are required

  • e.g.90% of population can be infected with EBV, but not many develop EBV related cancers

How can environmental / lifestyle interactions cause cancer?

• may affect how genes are expressed instead of the genes themselves

  • e.g. cigarette smoking, alcohol, poor diet, obesity, lack of exercise, UV exposure, ionizing radiation, pesticides, etc

What are tumour markers?

• substances produced by both benign and malignant cells that are either present in or on tumour cells, or found in blood, spinal fluid, or urine

  • e.g. prostate specific antigen (PSA) secreted by prostate tumours into blood at high levels

• helps identify high risk people, diagnose tumour, and follow treatment success

• possible to get false positives and negatives

• best for monitoring therapy success

What are types of cytology / histology for cancers?

• papanicolaou test / PAP test

• biopsy

• immunohistochemistry

What is a papanicolaou / PAP test?

• examines secretions around a tumour than can contain tumour cells

• can reveal abnormal cells

  • e.g. cervical, pleural, peritoneal secretions, etc

What is a biopsy?

• removal and examination of tissue sample

  • through a needle, an endoscope / laparoscope, or surgically

What is immunohistochemistry?

• use of antibodies specific to a cell product or surface marker

  • used to detect the presence of the product or marker

  • e.g. BRCAs can be sorted into 4 subclasses based on estrogen receptors, HER2/Neu, and other specific genes and proteins

• important in determining treatment

What are the different types of imaging used for cancer?

• endoscopy

• ultrasound

• x rays

• CT scan (computerized tomography)

• MRI scan

• PET scan

What is a CT scan?

• computerized tomography

• many x rays from different angles

  • fed through a computer to produce a 3D image

What is an MRI?

• magnetic resonance imaging

• used a magnetic field

• provides soft tissue detail

• more expensive and time consuming

What is a PET scan?

• positron emission tomography

• uses a biologically active molecule attached to a tracer

  • shows metabolically active tissue

What two ways can we identify cancers?

• grading (cellular characteristics)

• staging (spread)

• stage is better for treatment decision

What is grading?

• biopsy of tumour

• the closer the tissue resembles normal tissue, the lower the grade

  • grade 1 = well differentiated, close to normal, and slow growth

  • grade 2 = moderately differentiated

  • grade 3 = poorly differentiated

  • grade 4 = undifferentiated, abnormal cells, fast growth and spread

What is staging?

• includes size and spread of the disease

  • stage 1 = origin

  • stage 2 = local invasion

  • stage 3 = local lymph node invasion

  • stage 4 = spread to distant sites (e.g. liver cancer to a lung

What is chemotherapy?

• targets metabolic pathways

  • in hopes that a cancer cell is more sensitive to a particular chemical

  • e.g. leukemia is sensitive to folic acid deficiency, can treat with antifolate drug

Why is chemotherapy used in combinations?

• decrease dosage of any one drug to reduce side effects

• to increase attack on cancer cells

  • cells may be resistant to one drug but susceptible to another

What is induction?

• chemo given alone

What is adjuvant and neoadjuvant?

• adjuvant is after surgery to eliminate small metastasized tumours

• neoadjuvant is before surgery to minimize normal tissue removal

What is radiation therapy?

• targeted cells die from molecular damage by ionizing radiation

  • usually to the DNA

• most effective on rapidly renewing cells

• best for localized tissues in areas that are hard to reach surgically

• can be through external beams or placing small radioactive capsules in the affected area

  • brachytherapy

  • e.g. cervical, prostate, head, and neck cancers

What is surgery?

• best for localized tumours

• establishes grading and staging of cancer with biopsy

• may be used prophylactically

• pre cautions include avoiding spread of cancerous cells during operation