normal vs. cancer cells

what are some differences between normal and cancer cells?

• altered homeostasis

• changes in cell differentiation

• altered cellular metabolism

• DNA repair abnormalities

• angiogenesis

• alteration of tumor microenvironment to one that - encourages cell survival

• immune response changes

• metastasis

• changes in cell shape and motility

• altered responses to growth factors

what is altered homeostasis?

• in cancer, cells may grow and divide at a faster rate than they die
• involves increased proliferation, decreased apoptosis, loss of contact inhibition, or anchorage-independent growth

what is growth control?

• cell growth and division are under strict control in normal cells

• cells only divide when the body needs more cells

• in cancer cells, they can grow and divide uncontrollably, even when the body does not need more cells

how can increased/unregulated cell proliferation can occur?

by evading the process of replicative senescence

what is replicative senescence?

• many normal cells have a limit to how many times they can divide
• related to the shortening of telomeres

what is telomerase?

• an enzyme that maintains telomeres
• many cells are deficient in telomerase
• in most cells, telomeres constantly shorten at every S phase and cells eventually stop replication

how can cancer cells avoid replicative senescence?

• the reactivation of telomerase gene so that telomeres don't shorten
• alternative lengthening of telomeres (ALT): a DNA repair mechanism that elongates telomeres
• result: cancer cells may continue to proliferate while normal cells woud have stopped

what is the importance of apoptosis?

• normal cells undergo apoptosis when they become old or damaged
• too much or too little can lead to disease
• cancer cells often evade apoptosis and continue to grow even in the presence of apoptotic signals

how can cancer cells experience death?

• by necrosis
• can happen in the interior of a tumor where cells are not exposed to sufficient O and nutrients

what is contact inhibition?

• normal cells have contact inhibition
• they stop dividing when they come into contact with other cells
• cancer cells often lack this inhibition and can pile up on top of each other to form tumors

what is anchorage independent growth?

• loss of the requirement for adhesion to a surface
• most normal cells need to adhere to a surface in order to survive: important protection against cancer
• some cancer cells lose this inhibition and can continue to grow even when they are not associated with a surface
• cancer cells no longer require all of the (+) signals from their surroundings that normal cells require

what is the importance of anchorage-independent growth?

• cells that enter the lumen of normal structures in mammary epithelial tissue will undergo apoptosis: they have nothing to adhere to
• in cancer, cells in the lumen may continue to survive even when they are detached

what are changes in cell differentiation?

• normal cells are differentiated (carry out specific functions)
• cancer cells are often undifferentiated or poorly differentiated

what is the warburg effect?

• altered cellular metabolism
• tumors grow rapidly and have a high requirement for nutrients
• they consume a large amount of glucose
• they import glucose from the blood at rates up to 100-fold higher than normal cells
• the glucose is not metabolized the same way as normal cells
• most of the glucose is metabolized by glycolysis
• leads to rapid production of new building blocks of the cells (e.g. proteins and amino acids)

what are DNA repair abnormalties?

• normal cells have mechanisms to repair DNA damage
• cancer cells often have mutations that disrupt these mechanisms, leading to genetic instability and further mutations

what is angiogenesis?

• the formation of blood vessels
• normal cells do not generally promote the growth of new blood vessels
• cancer cells can stimulate the growth of new blood vessels: helps them obtain nutrients and O from the blood supply

what are the effects of angiogenesis in cancer?

• cancer cells cause new endothelial cells to grow

• can cause new projections to form sprouts from blood vessels, eventually allowing them to reach the tumor

what is the tumor microenvironment (TME)?

• the complex ecosystem of cells and molecules that surround the tumor, including the cancer cells themselves, the stroma, and immune cells
• the tumor depends on communication and cooperation with the stroma
• plays an important role in tumor growth and responses to treatment

what cells does the stroma include?

fibroblasts, immune cells, and vascular cells

what happens to the tumor microenvironment in cancer cells?

→ with some normal tissue, the stroma initially has fibroblasts and inflammatory WBCs and endothelial cells that make up vessels, and smooth muscle cells
→ as tumor progresses, the cancer cells change this environment by secreting signaling proteins that change the characteristics of the stroma cells and sometimes recruit/avoid certain cells
→ the cells also secrete proteolytic enzymes that modify the ECM in the stroma
→ in response, the stromal cells secrete signaling proteins that stimulate the cancer cells to divide, and proteases that further remodel the ECM
→ the tumor and stroma evolve together

what can be seen in the tumor microenvironment?

• tumor cells
• pericytes line blood vessel
• cancer-associated fibroblasts
• tumor-associated immune celles

what are immune response changes?

• normal cells are recognized by the immune system as self and are not attacked
• sometimes, cancer cells are recognized as foreign by the immune system and destroyed, but other times, cancer cells can evade the immune system's detection, allowing them to continue to grow and divide

how can tumor cells manipulate the immune system cells found in the stroma?

• some tumor cells can block the activation of immune cells (WBCs) that could kill them
• cancer treatments are being developed to block this inhibition

what are checkpoint molecules?

• PD-1 and other related receptors
• may help maintain a balance between the ability of the immune system to attack invaders, and the avoidance of attacking self-cells
• cancer cells may exploit the system by expressing proteins (e.g. PD-L1: shuts down the immune response from an immune cell)

what are the effects of some immunotherapy drugs?

• can target PD-1 or PD-L1
• allows for the killing of tumor cells by immune cells

what is keytrude (pembrolizumab)?

• a PD-1 inhibitor
• binds to PD-1
• approved for the treatment of melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, and others

what is metastasis?

multi-step process:

• cancer cells first invade local tissues and vessels
• cells then circulate through vessels
• cells eventually leave the vessels
• cells establish new colonies at distant sites

what is invasiveness in metastasis?

• an important first step
• the cell develops ragged borders and grows in a disorganized way
• the cell disrupts the adhesive mechanisms that normally keep it tethered to a surface
• the cell can then penetrate blood/lymphatic vessels and travel to distant sites

what is the establishment of distant colonies?

• can occur when the cells penetrate blood or lymphatic vessels again
• leaves the vessels and establishes new colonies
• after these events occur, only a small % of the cancer cells succeed in establishing new colonies

what is circulating tumor cells (CTC)?

• detected in blood sample for diagnostic purposes
• "CellSearch Circulating Tumor test": used to identify small amounts of circulating tumor cells in patients who have had certain types of cancer, to predict whether there is cancer remaining in the body

what have scientists learned about metastasis from mouse studies?

• show that some cells die immediately once entering the vessel or foreign tissue
• others survive entry into foreign tissue but fail to proliferate
• others divide a few times, then stop: forms micrometastases
• only very few establish full-blown metastases: fewer than 1 in a thousand or a million
• the final step in colonization seems the hardest: cells may fail to survive or survive for only a short time
• only a very small portion of cancer cells can survive the process of full metastasis

what are changes in cell shape and motility?

• cancer cells often change their shape

• may become more round

• may change into a shape that allows them to be more mobile, resulting in transit through the bloodstream and metastasis

what are altered responses to growth factors?

• cancer cells may change their responses to growth factors
• may overexpress growth factor receptors
• may have mutated growth factor receptors that no longer require a stimulus to be activated
• can often grow in low growth factor conditions, where normal cells would not be able to survive

what are some important targets of anti-cancer drugs?

PD-1 (immunotherapy), VEGF (to inhibit angiogenesis), BCL-2 (functions downstream to AKT and is important for cell survival)

what are carcinomas?

• cancers that derive from epithelial cells
• most common type of cancer (about 85%)
• the cells in these tissues are highly proliferative
• most normal cell proliferation happens in the epithelia

what does more proliferation mean?

more of a chance for developing mutations

what are cancers that derive from WBCs?

myeloma, leukemia, lymphoma

what are cancers that develop from connective tissue or muscle cells?

sarcomas

what are cancers that develop from the cells of the nervous system?

medulloblastoma, neuroectodermal tumors, gliomas, craniopharyngiomas, meningioma

what is adenoma?

• benign tumors
• derive from glandular tissue and have a glandular structure
• can potentially become malignant

what are basal cell carcinomas?

• come from a keratinocyte cell in the skin
• usually continue to synthesize cytokeratin intermediate filaments

what are melanomas?

• derived from pigment cells of the skin
• will often continue to make pigment granules

what are examples of cancer cells with different origins that have different characteristics and outcomes?

basal cell carcinomas of the skin rarely metastasize while melanomas are more likely to metastasize

what can cancer cells do?

• can reproduce without the normal restraints
• invade and colonize other tissues

what are benign tumors?

made up of cells incapable of invading and colonizing other tissues

what is the development of cancer?

• microevolutionary processes
• can start from a single cell as a result of DNA mutations

what gives rise to a primary tumor?

• some DNA mutations may cause a selective advantage, which can be dangerous
• a single cell with such a mutation can become a founder of a clonal colony of mutant cells

how can cancer start from a single cell with a DNA mutation?

• as the cells derived from this single cell grow, repeated rounds of mutations can take place in the cells within the clone
• if the cells continue to have a growth advantage, this clone of cells can propagate at the expense of its neighbors
• by the time it is detected, a tumor often has a billion or more cells
• in addition to primary cells, other cells are associated with the tumor (tumor stroma)

what is genetic analysis?

• is carried out to support the clonal origin of cancer cells
• e.g. identical mutations are usually found in all cells within a tumor, strongly suggesting a common origin

what is the importance of the philadelphia chromosome?

• the discovery of the chromosome translocation was pivotal for understanding the clonal origin of cancer because every CML cell in a patient had the same mutation
• this indicated that the mutation originated from a single cell
• consists of a translocation between chromosomes 9 and 22
• led to a fusion between the Abelson (Abl1) gene on chromosome 9, with the breakpoint cluster region (BCR) on chromosome 22
• led to the development of Gleevac (imatinib): targeted BCR-Abl, which is the first targeted therapy for cancer and significantly improved patient outcomes

what are somatic mutations?

• primary cause of cancer
• agents that can cause genetic mutations can be carcinogens
• carcinogenesis is linked to mutagenesis

what are chemical carcinogens?

• can cause simple changes to DNA
• radiation (e.g. x-rays) can cause chromosomal breaks and translocation
• UV light can also cause mutations in DNA

what are germ line mutations?

• inherited mutations
• can cause some types of cancer (~5-10%)

what is the rate of mutation?

• about 10^16 cell divisions occur within the body over a lifetime
• mutations occur naturally during cell replication, even without mutagens

why is cancer not more common than it is?

• the risk of cancer increases with age, most likely due to an accumulation of genetic mutations
• even after exposure to carcinogenic agents, cancer can take years to develop, suggesting that an accumulation of mutations is required for the development of cancer

what is tumor progression?

occurs over time, during which new mutations have a chance to develop

what is the process of tumor progression?

→ a cell develops a selective advantage and grows more rapidly than its neighboring cells
→ as these cells progress, some cells acquire additional mutations that give them an even better advantage
→ the larger the number of replicating cells, the better chance for the development of mutations with even better selective advantages
→ as a tumor grows, progression accelerates
→ over time, the original cancer cell and its offspring can diversify even more, to give rise to many genetically different subclones of cells

what are the effects of how cancer cells can evolve quickly?

• although initial development is usually gradual, there can also eventually be sudden increases in new changes
• cancer cells over time can become "genetically unstable" and in turn can accumulate mutations at a rapid pace
• the extent of this instability varies among different types of cancer
• changes can be large (seen in karyotype) or smaller genetic changes

what chromosomal changes in colon cancer cells that occured as a result of genetic instability?

• the karyotype of a typical cancer shows many gross abnormalities in chromosome number and structure

• the karyotype of a tumor that has few chromosomal anomalies

what is a karyotype?

a visual representation of the complete set of metaphase chromosomes in the cell