BIOL 465 - Molecular Basis of Cancer: Lectures 1 & 2

Breast cancer - Contributors and facts

- Affected by estrogen levels, which influence the mitogenic pathways - Estrogen binds to promoters (as transcription factors) - Uncontrolled levels of estrogen increase your risk of cancer, esp breast e.g. EsRa breast cancer = Estrogen Receptor alpha - binds to the estrogen response element (ESE) - Much more prevalent in Uruguay (10X), followed by US

Examples in which there is a poor correlation btwn cancer severity and cell division frequency (3)

- Brain tumors tend to divide relatively slowly. Still, the rate of division doesn't indicate how aggressive the tumor is going to be. - Smal intestinal tumors are rare, yet the cells divide rapidly (i.e. avg human being produces ~40kg GI cells/yr & 10kg of WBC's) - A patient can die from a tumor weighing less than 5kg that took years to develop!

d) Neoplasia

- Characterized by disorganized cell growth - Net increase in number of dividing cells Is now metastatically capable. Immune cells have recognized this cancerous cell and are now building a memory for it., but may eventually contribute to neoplastic capabilities.

Why could it be that Japan has a 14x greater incidence of Stomach caner?

- Diet & nutrition play a major role in contributing to cancer, esp w/ stomach cancer. - Processing of food products e.g. Nitrosamines - in pickled, smoked or cured meats; carcinogenic. - Balance of antioxidants? - Our bodies lack the genetic background (aren't evolutionarily adapted to deal with these processed foods) - e.g. These products are broken down much more rapidly compared to more complex/wholesome foods.

Liver cancer - Contributors and info

- Has very important genetic factors - Storage of too much iron in the liver predisposes you to hepatocellular carcinoma - Infection (chronic/persistent) is also a big contributor --> dysplasia of hepatic tissue --> liver cancer! - e.g. Uncontrolled hepatitis C & E. Prevalent in Argentina (75X)

What is meant by "Cancer is a disease of aging"

- Incidence rate of [age specific] cancer markedly increase w/ age. Reaches peak at 75 years. - Still comes back to our ability to repair DNA damage. Accumulation of this damage much greater as time passes... Therefore, age is a very important predictor for cancer --> accumulation + decreased ability to repair.

Tumor cell pathology - i.e. characteristics (7) Nuclear size & shape, N/C ratio, mitotic index, tissue organization, level of differentiation, tumor boundary

- Nuclear size: Large (lg amount of nuclear division occurring) - N/C ratio (ratio of nuclear size to cytoplasmic volume): High - Nuclear shape: Pleomorphic (irregular shape); high livels of nucleotide reductase present to rapidly elicit mitosis, etc. - Mitotic index (rel # of dividing cells): High - Tissue organization: Disorganized - Differentiation: Poorly differentiated (anaplastic) Tumor boundary: Poorly defined (i.e. not "encapsulated"); utilize proteolytic enzymes to surpass the encapsulation by basement membrane/collagen)

What can be used to describe the shift of high incidences of Stomach cancer in males in Japan to high incidences of Colon cancer in Sons of male Japanese immigrants to California?

- Reinforces the fact that Behaviour and environment are important contributors to cancer - Change in diet away from nitrogen-cured meats. Now leaning towards a diet lacking in fruits and vegetables (less fiber) --> alters microbiome, as well as more processed foods. --> Contributes to colon cancer.

Examples of Environmental factors

- cloud cover (protection from UV rad) - time of day when exposed to UV light (more intense in afternoon) - environmental contaminants/pollution - blue light pollution

What are some visual indicators that a mass is cancerous?

- irregular pigmentation - irregular shape (i.e. no proper margins) - level of keratinization Indicate that these cells have not be controlled by apoptosis & would not have the normal differ'n of their native/original tissue. - Likely due to DNA repair mechanism or uncontrolled kinase activity

Process of Metastasis from Primary Tumor (3)

1) Cancer cells invade surrounding tissues and vessels (i.e. Become dysplastic --> are able to invade/ surpass basal lamina). 2) Cancer cells are transported by the circulatory system --> lymphatic system. The lymph nodes come into contact with anything draining from these regions, notifying the immune system. 3) Cancer cells reinvade & grow at new location

What are the 2 theories/hypotheses for preferred sites of cancer metastasis?

1. Seed & Soil Hypothesis (Paget, 1889): The pattern of metastatic spread of cancer is not random and that cancer cells exhibit preferences when metastasizing to organs. i.e. Certain tissue/organs are particularly favorable for the growth of some cancers. 2. Capillary bed entrapment: Organ preference is a fn of entrapment of cancer cells in the first capillary bed encountered. Probably depends on both a mechanical sieving effect AND the presence of specific environmental conditions.

Prostate cancer - Contributors & info

106X more common in U.S. Also typically more prevalent in European countries & Canada. Affected by the testosterone:estrogen ratio. Dependent on the microenvironment of where the tumor is growing (likely large LOCAL levels of testosterone; not necessarily levels in the blood). Elevated testosterone levels increase the risk for benign prostatic growth, which increases your risk for prostate cancer - e.g. injections/exogenic sources.

What is Cancer?

A collection of related diseases of proliferation - i.e. is not one entity/disease. - Each cancer shares a proliferative & metastatic capacity, but they vary in terms of their ability to de-differentiate, etc. - In all types of cancer, some of the body's cells begin to divide w/out stopping & spread into surrounding tissues - Differ from normal cells in that they are less specialized than normal cells --> less specialized; loss of original fn

What is an exception to "Cancer is a disease of aging"?

Acute leukemia Most people are ages 3 to 18 years Involves lymphocytic & myeloid cells Much less common in older people!

What is tumor growth an imbalance of?

An imbalance between cell division, cell death & cell differentiation i.e. An altered ratio - too much cell birth/division or too little cell death

Tumor definition

Any abnormal growth (neoplasm) or mass of tissue which exceeds and is uncoordinated w/ that of the normal tissue and persists in the same excessive manner after cessation of the stimuli which evoked the change Can be benign or malignant

Why do tumor cells essentially accumulate?

Because of failure in differentiation OR block of apoptosis (regular cell death)

What cancers are prevalent in Canada, US, Brazil, UK,China, Japan, and Australia?

Canada - Leukemia US - Colon Brazil - Cervical UK - Lung China - Liver Japan - Stomach Australia - Skin

What is the leading cause of death in Canada?

Cancer (29.9%) Then Heart disease (19.7%) - is much greater globally though Values based on WHO Report

A "non-invasive" cancer can also be known as...

Carcinoma in situ

c) Dysplasia

Characterized by disorganized cell growth

Why is it that certain cancers frequently metastasize to specific sites?

Depends on location of cancer. Also depends on certain receptors that cancer cells are attracted to.

Geographical distributions of cancer - indicative of cause?

Effects of the environment (due to geograhical distributions) is esp important b/c we're drastically altering the environment, which changes the risks. e.g. more UV light in Australia w/ breakdown of ozone layer--> greater incidence of skin cancer.

Why is geographical variation so important in terms of figuring out cancer incidence?

Geographical variation is indicative of... - environmental, - genetic, and - behavioural causes

What makes the dark-pigmented mass (malignant melanoma) a cancer (i.e. invasive tumor)?

Has started to spread away from the normal basement membrane of the tissue. Would observe infiltration by immune (T) cells in this area due to presence of inflammation. Can become MOBILE and will de-differentiate. Could even have lymph node involvement at this stage

How are cancer cells similar to stem cells?

Have the ability to divide and give rise to progeny that possess a certain characteristic for prolific growth Are both technically undifferentiated - i.e. cancer cell typically undergo dedifferentiation

b) Hyperplasia

Increase in cell number Normal organization

a) Hypertrophy (2 examples)

Increase in cell size Normal organization e.g. w/ the breasts during menstruation e.g. w/ muscle during increased freq of exercise

Hypothesis for prevalence of Leukemia in Canada?

Increased levels of radon, less UV light in northern environment? The more north you are, the more sensitive you are to certain types of cancers... especially chronic leukemias (correlate to aging). Lack of Calcitriol (Vitamin D) thought to be a major contributor

Why are the lungs and liver favoured by numerous types of cancers?

Lungs have a very rich capillary network. The entire circulatory system passes through the lungs!!! The liver is also highly vascularized

Does the SIZE of a tumor determine its malignancy?

NO Size, technically speaking, dose not determine malignancy. Also, the detrimental effects really depend on location of tumor. e.g. a small tumor on the spine or in the brain can have a substantial negative effect.

The microenvironment of a (primary) tumor - e.g. other cells/factors involved (7)

Not solely made up neoplastic cells. For example, can consists of... - Fibroblasts (tumor-associated fibroblasts) - Immune cells (e.g. tumor-associated macrophages or TAM's) - Resident adipocytes - Increase in levels of inflammatory mediators /cytokines, esp those derived from immune system. - Endothelial cells (line vasculature) --> angiogenesis to form more capillaries in select area to provide more oxygen and nutrients to cancer cells/tumor - A lot of this info due to studies by Hardy Weinberg

Four types of cancers and their common sites of metastasis?

Prostate --> Bone Small Cell lung --> Brain Neuroblastoma --> Liver Breast --> Liver

"Stages" of breast cancer (6)

Stage 0 (100% survival): Non-invasive carcinoma in situ Stage I (98%): Invasive tumor (<2cm), no lymph node involvement StageII (88%): Tumor's size <5cm & >2cm or has spread to lymph nodes (i.e. has mobile capacity) Stage IIIA (56%): Tumor >5cm or lymph nodes are clumping Stage IIIB (49%): Any size tumor that has spread to skin, chest wall or mammary lymph nodes Stage IV (16%): Any invasive tumor that has spread beyond the breasts & lymph nodes

Metastasis

The spread of cancer cells beyond their original site The process through which the cancer establishes itself at another site(s) Spreading of cancerous cells from primary tumor Cancer cells are attracted to a particular tissue due to certain features (e.g. extracellular matrix receptors, endothelial cell receptors, etc.)

Can you die from a benign tumor?

Yes. Even if it's benign. If the size is too large and it's impeding normal autonomic function, for example, it can be fatal. Can still "invade" other tissue space. A benign ovarian cyst (adenoma) could occlude the aorta, for example. i.e. can cause death if they impede the normal functioning of essential tissues/organs

Four types/stages of cell growth (leading to neoplasia)?

a) Hypertroph b) Hyperplasia c) Dysplasia d) Neoplasia

Which two stages/types are due to external stimuli and are reversible?

a) hypertrophy b) hyperplasia It's the CHRONIC change in these characteristics that could lead to dysplasia/cancer.

Which stage/type of cell growth is characterized by Disorganized growth and May or may not be reversible?

c) Dysplasia There would be evidence of some benign hypertrophy (e.g. fibroblasts, tissue disorganization), that would remain as a 'scar' (if reversed).

What type/stage of cell growth is considered to be a tumor, with no stimuli required, and is NOT reversible?

d) Neoplasia

Stem cells

unspecialized cells that retain the ability to become a wide variety of specialized cells Are unspecialized cells capable of renewal and proliferation Have the ability to divide and give rise to progeny that possess a certain characteristic for prolific growth

Summary of Introduction to cancer (7)

•Cancer is a collection of related diseases of proliferation. •Cancer statistics are different dependent on country •Cancer is a disease of aging and in some types of the young. •Behaviour and environment are important contributors. •Metastasis is a part of malignancy. •There is an imbalance between cell division cell death •Size is not a predictor of malignancy.