Cancer :D

From hallmarks, NMR paper, therapies and everything in between :)

Definition of cancer

Definition of cancer

family of diseases with like feature; abnormal and uncontrollable cell division

metastasis

The spread of cancer cells beyond their original site

Evolutionary Principles of Cancer

1. Somatic Selection shapes malignancy*

Somatic selection shapes malignancy

natural selection among cancer cells; most prevalent principle

frequency of cancer

second most common cause of death, behind heart disease

Why does cancer frequency increase over time?

life span is increasing, and cancer & heart disease are common among the elderly

most common forms of cancer

breast, lung, prostate

most common deadly forms of cancer

lung, then prostate & breast

metastasis...

increases risk of death

primary route for metastasis

circulation & travelling somewhere else via lymphatic nodes most often

what distinguishes cancer cells from normal cells

behavior

Hallmarks of Cancer (circa 2022)

resisting cell death

Hallmarks of Cancer (circa 2022)

deregulating cellular metabolism

Hallmarks of Cancer (circa 2022)

unlocking phenotypic plasticity

Hallmarks of Cancer (circa 2022)

sustaining proliferative signaling

Hallmarks of Cancer (circa 2022)

evading growth suppressors

Hallmarks of Cancer (circa 2022)

nonmutational epigenetic reprogramming

Hallmarks of Cancer (circa 2022)

avoiding immune destruction

Hallmarks of Cancer (circa 2022)

enabling replicative immortality

Hallmarks of Cancer (circa 2022)

tumor-promoting inflammation

Hallmarks of Cancer (circa 2022)

polymorphic microbiomes

Hallmarks of Cancer (circa 2022)

activating invasion & metastasis

Hallmarks of Cancer (circa 2022)

inducing angiogenesis

Hallmarks of Cancer (circa 2022)

senescent cells

Hallmarks of Cancer (circa 2022)

genome instability & mutation

how does somatic selection shape tumor cell behavior

1.natural selection selects certain cells to be more potent & therefore easier to grow 2.genome instability causes changes in DNA can be selected for 3. increased bioenergetics through angiogenesis

selection pressure

an environmental variable that acts to remove poorly adapted phenotypes

oncogene

a normal gene that has changed into a cancer-causing gene with a hyperactivating protein; GOF in cancer cells

tumor suppressor

A gene that codes for a protein product that inhibits cell proliferation; LOF in cancer cells.

p53 gene

a tumor-suppressor gene that codes for a specific transcription factor that promotes the synthesis of proteins that inhibit the cell cycle

p53 activation

UV rays that cause p53 protein to increase transcriptional targets for apoptosis

Apoptosis

programmed cell death (evolutionarily conserved)

why is apoptosis conserved?

to maintain homeostasis and keep the immune system in check

why is death orderly and highly regulated?

important because there should not be chaotic cell death; cells could sparingly die if unregulated; could be beneficial for cell

Ced-9

oncogene that inhibits apoptosis when turned on

Bcl-2

Oncogene that blocks apoptosis

DCIS (ductal carcinoma in situ)

abnormal cells in milk duct; CAN LEAD to cancer

Blc-2 effects:

1. delays cell death

2. BUT cannot completely inhibit apoptosis

relationship between cell death and natural selection

there are redundant forms of cell death to prevent infinite proliferation

why do cells die with Bcl-2?

cells can be defective in taking up glucose, metabolic changes and high levels of oxidative stress

Catabolism

Metabolic pathways that break down molecules, releasing energy.

Anabolism

Metabolic pathways that construct molecules, requiring energy.

what metabolic changes are expected in cancer?

1. high rates of ATP

2. high uptake of glucose

3. lots of lipid uptake

4. glutamine is ramped up

cancer cells, even when there is oxygen present...

elect to do aerobic glycolysis (can serve as a signal where there are waste products)

Warburg effect

-use of glycolysis under normal oxygen conditions (aerobic glycolysis) -allows products of glycolysis to be used for rapid cell growth -activated by oncogenes and mutant tumor suppressors -consuming high levels of glucose

Cancer metabolism

-deregulated uptake -opportunistic (steal nutrients) -biosynthesis (metabolic flux) -increased demand for nitrogen -interaction w/ microenvironment -alterations in metabolite-driven gene regulation -Warburg Effect (PET imaging is helpful)

NSCLC

imaging shows lots of glucose and tumors in lungs (place where should be low glucose presence)

how does cancer metabolism relate to evolutionary principles

more angiogenesis, more anabolic needs, and niche construction (interaction with microenvironment & competition/cooperation)

Intratumor heterogeneity

mixture of genetically distinct regions in a single tumor; leads to competition and cooperation (example is cooperative breeding in birds)

ECI

early contact inhibition (cells stop growing once plate is full); very prevalent in naked mole rats (NMR)

p16

promotes very early ECI in NMR

p27

promotes regular ECI in humans and mice

Questions used to analyze figures and papers:

1. What was their question?

2. What did they do? 3.What did they find?

3. What does it mean?

NMR Figure 1

HAS1, 2, and 3 are known for making HA; when NMRSF in culture, there was highly viscous media; CORRELATION in viscosity and ECI; link viscosity to HA; HAase causes low viscosity-->leads to next figure

NMR Figure 2

analyze Haase abilities; find that NMR HMM-HA is not being degraded in comparison to other species

NMR Figure 3

by eliminating HA, through HAase degradation, you can eliminate ECI; amount of HMM-Ha is relevant in ECI (ECI present with HMM-Ha present)

NMR Figure 4

confirming presence of HMM-HA inhibiting tumor formation; found minimum number of things to make robust growth

NMR main takeaways:

-HMM-HA is the key in NMR resistance to tumorigenesis -inhibiting HMM-HA production causes cancer

HAS2

protein elevated in NMR

Haase

protein that inhibits HMM-HA production

HMM-HA

presence inhibits cancer

Cd44 mutation

major HA receptor; formation of tumor microenvironment

In order to have robust, tumorigenic growth, you need:

1. oncogene like RAS

2. inhibit TS pathways

3. get rid of ECI with the introduction of HAase

if something is necessary for robust growth...

usually answered as one of the three since you NEED all three, you need each one

If something is sufficient for robust growth...

the presence of all 3 (?)

three most common treatments for cancer:

1.surgery 2.radiation 3.chemotherapy

Strengths and Weaknesses of Surgery

S: usually happens only once; does not kill normal cells; minimal side effects; good for early stages

W: cancer cells can still remain in tissue, which can lead to prolonged tumor growth; still invasive;

Strengths and Weaknesses of Radiation

S: kills cancer cells and shrinks any tumors; extremely localized; minimizes harming other tissues

W: some possibility of extraneous DNA damage; more deadly cells can survive; need all cells dead (one evolved cancer cell can weaken radiation)

Strengths and Weaknesses of Chemo

S: stops rapid cell division; more permanent than surgery; can be use for cancers that are not in one location (metastasized)

W: side effects are brutal; cancer can potentially evade and evolve; repeated exposure and prolonged

Chemo + Surgery

highly effective to remove primary tumor then use chemo to eliminate metastasis

targeted cancer therapy

focuses on a molecular level, not on tissues

Gefitinib (Iressa)

GOF in the EGFR receptor; effective for NSCLC; is a receptor tyrosine kinase (RTK); catalyzes addition of phosphate

Trastuzumab (Herceptin)

used in breast cancer patients w/ high levels of HER2; antibody that binds to cell surface and disrupts downstream signaling

mRNA COVID-19 vaccine

mRNA sequence into cell-->spike protein translated-->immune system recognizes spike protein-->memory-based immune response

Bevacizumab (Avastin)

used in metastatic colorectal or lung cancer; VEGF (a known oncogene) inhibitor; binds to VEGF and prevents it from binding to the corresponding VEGF receptor

Strengths and weaknesses for targeted therapy

S: highly localized in certain patients; targets primary origin; no harmful side effects; opportunities for precision medicine

W: specific for certain types of cancer; attacks processes behind proliferation; could be redundancies; very expensive

CML (chronic myelogenous leukemia)

long chromosome 22 and short chromosome 9 have a chromosomal translocation-->shorter 22 and longer 9; results in creation of Bcr-Abl that drives CML

Imatinib (Gleevec)

inhibitor of Bcr-Abl; effective for CML; inhibits kinases that are related to the ABL Tyrosine Kinase; highly effective

potential barriers to developing new therapies

cancer is a community of different cells; money; too many different cell types to make a highly effective therapy; need to find molecular composition before therapy

targeted therapies work well in

cancers where there is no/more cancer than just a primary tumor; niche forms of cancer; pathway alterations

modified herceptin

contains sialidase to remove sialic acid sugar; binds to receptor like normal herceptin and cleans off sugar for immunotherapy to be more effective

sialic acid

makes cancer cells more resistant to immune recognition

HIF1alpha in normoxia

proline hydroxylase adds O2 and pVHL begins degradation process

HIF1alpha in hypoxia

accumulates + binds to HIF1b for increased transcription of VEGF

Heterotypic interactions

interactions among different types of cells; consider how cellular mechanisms are corrupted in cancer cells + tumors contain all cell types

Stromal cells

Cells that contribute to the development of multiple tissues and blood cells; leads to heterotypic interactions

experiments/research with heterotypic interactions

consider xenograft experiments where epithelial cells (white and circular) are surrounded by stromal cells

xenograft

P: see cells in physiological conditions and get a baseline about tumor formation

C: not natural environment; does not mimic patient as well

cells grown in culture

P: can be hyperfocused; readily observable + testable

C: not natural environment; not even close to a patient's body

genetically engineered mouse models

P: tumors develop naturally; straightforward and doable

C: risky to change germ line; does not perform well with manipulations

bioinformatics

P: little risk for studying human data

C: not in real time; lack of reliability + subjectivity

clinical trials

P: getting human physiological data in real time; tremendous power

C: can be quite risky; risking lives of patients; have to consider variations among types of cancer; cannot easily manipulate across types

Evolutionary Principles of Cancer

2.ecological principles explain how cancers interact with microenvironments

Evolutionary Principles of Cancer

3. behavioral ecological principles explain competition and cooperation among cancer

Evolutionary Principles of Cancer

4. natural selection explains why cancer is rare

Evolutionary Principles of Cancer

5. evolutionary medicine explains why cancer is common