LECTURE 4-CANCER AND CANCER STEM CELLS

Key concepts from lecture 3 on stem cells

• different types of pluripotency

• definition of stem cell (what makes a stem cell?)

• definition of stem cell niche

• adult stem cells

  • intestinal epithelial stem cell niche

  • neural stem cell niches

  • epithelial stem cell niche

  • hematopoetic stem cell niche (bone marrow)

  • WNT signaling (yes)

• concept of nuclear reprogramming

  • gurdon’s experiment

  • key factors used by Yamanaka for induced pluripotency

  • Yamanaka’s experiment

Overview: Cancer and Cancer Stem cells

1) fundamentals of oncogenes and tumor suppressor genes

2) metastasis requires invasiveness and migration

3) some tumors contain cancer stem cells (CSCs) also called tumor-initiating cells (TICs)

4) Novel aspects of tumorigenesis and metastasis

Original Hallmarks of Cancer

• telomerase: as the cell divides the telomeres shorten, this enzyme adds protective caps at the ends of chromosomes by adding repetitive DNA sequences

What causes cancer-factors associated with cancer risk?

1) genetic mutations

2) epigenetic dysregulation

3) environmental exposures

4) lifestyle factors

5) viruses

Proto-oncogenes (before alteration, afterwards it is oncogene) normally regulate…

• cell growth and proliferation and when mutated can cause cancer

• Oncogene examples: MYC and RAS

• MYC=normal protein greatly overproduced

• RAS=hyperactive protein made in normal amounts

Oncogenes require only…

• a single mutation to change function!

Activated Ras is mutated in…

• 30% of human cancer

• EGF=mitogen

• Mitogen activated protein kinase (MAPK)

• single point mutation at G12V in one copy of Ras gives cell selective advantage to proliferate uncontrollably

Proto-oncogenes are genes that when…

• mutated can cause cancer

• Myc normally promotes cell proliferation but is amplified in many human cancers

Tumor suppressor genes normally…

• negatively regulate cell division

• Two hit hypothesis: both copies of a tumor suppressor gene must be inactivated for the efficient tumor growth

• tumor suppressor genes—> p53, Rb (retinoblastoma), APC (adenomatous polyposis coli)

Normal balance between cell division and apoptosis is absent in…

• cancer!

• or both increased proliferation and decreased apoptosis

A malignant tumor contains cells with…

• multiple mutations in oncogenes and tumor suppressor genes

• APC=adenomatous polyposis coli

  —>familiar colon adenocarcinoma

A malignant tumor contains cells with multiple mutations in oncogenes and tumor suppressor genes

• tumor progression model in colorectal cancer (vogelstein 1990s)

The canonical Wnt signaling pathway is disrupted…

• in human cancers

• both copies of APC are inactivated-no need for signal + or -

Cancer is not just increased cell survival and proliferation: it also involves…

• invasion and metastasis

Cancer is not just increased cell survival and proliferation: also involves invasion and metastasis

Extracellular Matrix and Epithelial mesenchymal transition (EMT) in animals

• Epithelial cadherin=E-cadherin

Metastasis requires…

• epithelial cells to invade neighboring tissue, enter blood supply and colonize distant organs

What determines where the metastasized cancer ends up?

• Location: breast cancer cells usually go to the lymph nodes because of proximity

• Organ environment-bone provides a good environment for prostate cancer cells

• Priming: signals send from the primary tumor could start to create a favorable microenvironment for cancer cells to colonize an organ/tissue

Telomerase Reactivation and cancer cell immortality

• Telomerase: TERT(will become suppressed) subunit acts as a reverse transcriptase, TERC subunit provides template for telomere extension

• Healthy somatic cells: Telomeres shorten with each cell division and TERT is suppressed to prevent unchecked cell division leading to cell death senescence

• Cancer cells: Telomerase reactivates allows for continuous cell division that accumulates mutations by unchecked DNA damage repair of chromosomal abnormalities

  

What are the newer hallmarks of cancer cells?

Genomic instability…

• aneuploidy and translocations are hallmarks of cancer cells

Tumor Microenvironment and Cancer Stem Cell (CSC) hypothesis?

• tumor microenvironment

GBM stem cells are …

• resistant to therapies

• Glioblastoma multiforme (GBM)

• highly aggressive brain tumor

• median survival ~15 months

• US incidence 2-3/100,000 individuals

How can cancer stem cells be eliminated?

• current cancer therapies use anti-proliferative drugs or radiation

• cancer stem cells:

  • may not be dividing (quiescent)—>can kill neurons so need a precise delivery approach as neurons are also non-dividing

  • can have increased levels of drug efflux pumps

  • maintain high capacity to repair DNA

  • may be highly resistant to stress

How can cancer stem cells be eliminated?

• potential therapeutic strategies to target cancer stem cells:

  • develop drugs to target non-dividing cells

  • awaken quiescent cancer stem cells, then eliminate them

  • induce differentiation of cancer stem cells

Hallmarks of cancer cells: circa 2022

Latest hallmarks of cancer cells: unlocking phenotypic plasticity

Latest hallmarks of cancer cells; non-mutational epigenetic reprogramming

Latest hallmarks of cancer cells: non-mutational epigenetic reprogramming

• E-cadherin can go back in forth from the epithelial and mesenchymal cells—> inhibits cancer progression as it is a transmembrane glycoprotein

Latest hallmarks of cancer cells: Polymorphic microbiomes #1

• colon cancer: cancer protective and tumor promoting microbiomes

Latest hallmarks of cancer cells: Polymorphic microbiomes #2

• microbes could promote DNA damage or chronic inflammation

• unrepaired DNA damage could lead to mutations

• inflammation could alter tumor microenvironment promoting tumor growth or metastasis

Latest hallmarks of cancer cells: Polymorphic microbiomes #3

• Fecal microbiata transplant overcomes resistance to anti-PD-1 therapy in melanoma patients

  • instance where microbes can be beneficial

Current therapeutic approaches to cancer

Anti-PD1 Therapy

• PD-1 programmed cell death protein 1-found on T cells

• PD-1 acts as an inhibitory checkpoint preventing T cells from attacking other cells