Intro to Tumor Biology

Question 1

compare cell cycle control normal cells and cancer cells

Answer 1

in normal cells: growth and proliferation is tightly controlled; checkpoints control progression from phase to phase, progression through these checkpoints is tightly regulated and the decision to process results when there are more factors favoring progression than arrest

cancer cells: failure of cell cycle control leads to inappropriate cell cycle progression

Question 2

describe multiple hit hypothesis of carcinogenesis

Answer 2

1. mutations are common in cancer, especially to proteins that drive the cell cycle forward or modify cell cycle checkpoints
2. however, one mutation to one protein usually isn’t enough; instead multiple hits to multiple proteins are usually needed where each hit results in the cell acquiring proliferative capacity and/or other abilities (probably why we see cancer more in older patients, it takes time to acquire all these hits)

Question 3

define proto-oncogene, oncogene, and tumor suppressor

Answer 3

proto-oncogene: cellular component that controls proliferation; highly regulated in normal cells

oncogene: mutated or otherwise activated proto-oncogene, activated via mutations or overexpression

tumor suppressors: identify problems (DNA damage or other cellular problems) at cell cycle check points and mediate repair attempts; if unrepairable, tumor suppressors activate cell death pathways (usually apoptosis)

Question 4

justify why cancer is called a genetic disease

Answer 4

modifications of genes lead to cancer; these modifications are usually mutations, can be heritable or acquired, but the modifications to GENES lead to unregulated growth via multiple mechanisms

Question 5

describe carcinogenesis and give examples of different carcinogens

Answer 5

1. carcinogenesis: formation of cancer, changes of normal cells to cancer
2. mechanisms:
   -intrinsic: mistakes in routine DNA replication, defects in DNA repair, inherited mutations, chronic inflammation, hormone exposure
   -extrinsic:
   -chemical (secondhand smoke, living near industrial areas, pesticides and herbicides, hormonal)
   -viral: FeLV, FeSV, BLV
   -radiation

Question 6

list and explain the 6 original hallmarks of cancer

Answer 6

1. self-sufficiency in growth signals: most cells sit in G0 (resting phase) awaiting a signal to enter the cell cycle, but cancer cells acquire the ability to enter the cell cycle in the absence of a signal or by making the signal themselves; can do this via mutations that affect structure or overexpression of receptors that bind growth factors
2. resistance to anti-growth signals: DNA damage or other cellular problems lead to cell cycle arrest as cell cycle check points; mediated by tumor suppressors; loss of tumor suppressor function leads to uncontrolled proliferation (ex. p53)
3. evasion of apoptosis: cancer cells evade via
   -mutations to the proteases that mediate apoptosis (caspases)
   -upregulation of proteins that inhibit apoptosis
   -impaired signaling of receptors that initiate apoptosis
4. invasion and metastasis: most clinically relevant hallmark of cancer! some tumors are only locally invasive, but some are highly metastatic
5. sustained angiogenesis: cells die if they are >200um from a blood vessel, so a tumor cannot grow beyond 1mm without angiogenesis; cancer cells express VEGF (vascular epithelial growth factor)
6. replicative immortality: come cancer cells can express telomerase or telomerase like enzymes to extend their telomeres and be immortal

Question 7

what are the 2 major routes of metastasis?

Answer 7

1. hematogenous: via blood vessels; most common target is the lungs (but can als be the liver/spleen); sarcomas commonly spread via this route
2. lymphatic: via lymphatic channels; most common target is lymph nodes; round cell tumors and carcinomas commonly spread via this route

Question 8

describe the metastatic cascade

Answer 8

1. invasion/migration
2. intravasation/extravasation

most tumors can do 1 and 2

3. premetastatic niche: makes tumors happy, gives them nutrients and immune evasion, but is less common for a tumor to find this happy home
4. distant growth (fuckity uppity bit)

Question 9

define paraneoplastic syndrome and list examples

Answer 9

1. distant manifestations of cancer mediated by soluble factors released by the tumor or tumor stimulating the immune system to attack normal
2. most common paraneoplastic syndrome is hypercalcemia!: tumor cells secrete parathyroid related protein, which stimulates calcium conservation via the kidney and increases bone turnover
3. other examples include:
   -hypoglycemia: insulin secreting pancreatic tumors
   -thrombocytosis: dogs with liver tumors
   -paraneoplastic alopecia: cats with pancreatic tumors
   -myasthenia gravis: dogs with thymomas
   -disseminated intravascular coagulation (DIC): dogs with hemangiosarcoma