Hallmarks of Cancer & Telomeres

Why is conceptualizing cancer complex?

• There are >100 distinct types of cancer and many tumor subtypes within organs

• Each type may involve different disrupted regulatory circuits

What key questions arise about cancer regulation?

• How many circuits must be disrupted for malignancy?

• Do all neoplasms disrupt the same circuits?

• Which circuits act cell-autonomously vs depend on microenvironment signals?

• Can the vast array of cancer genes be linked to a few core regulatory circuits?

What did Hanahan and Weinberg propose in 2000?

The wide variety of cancer genotypes reflects six essential alterations in cell physiology that malignant growth

What does each physiologic change represent?

The successful breaching of intrinsic anticancer defense mechanisms built into normal cells and tissues

How did Hanahan and Weinberg describe cell signaling?

As an “integrated circuit” similar to electronic circuits — proteins (e.g., kinases, phosphatases) act as transistors, and phosphates/lipids act as signals

What are examples of component circuits in cells?

• Growth signaling (e.g., Ras pathway)

• Antigrowth and differentiation signaling

• Apoptotic control circuits

What happens when this integrated circuit is genetically reprogrammed?

Functional alterations in cancer-related genes disrupt normal control of cell growth, division, and survival

What was added in Hallmarks of Cancer: The Next Generation (2011)?

• Greater emphasis on tumor microenvironment (TME)

• Recognition of cancer stem cells (CSCs)

• Focus on the complex interplay between tumor and host factors

What additional perspective was provided by Hallmarks of Cancer: New Dimensions (2022)?

Integration of systemic and environmental factors influencing tumor development and progression

What are key processes in tumor progression?

• Angiogenesis (formation of new blood vessels)

• Metastasis (spread to distant tissues)

How is tumor progression affected by the microenvironment?

• Cancer cells interact with immune, stromal, and vascular cells

• Systemic factors (e.g., metabolism, inflammation) influence tumor behaviour

What hallmark allows cancer cells to divide indefinitely?

Replicative immortality — the ability to bypass normal senescence and death limits

What is the Hayflick limit?

The finite number of times a normal somatic cell can divide before senescence due to telomere shortening

How do cancer cells circumvent the Hayflick limit?

By overriding cell cycle control and maintaining telomere length through telomerase activation

What is the function of telomeres?

• They protect chromosome ends from degradation and fusion

• They shorten with each DNA replication cycle

What happens when telomeres become critically short?

• Chromosome ends are perceived as double-strand breaks (DSBs)

• The cell erroneously “repairs” them, leading to chromosomal breakage–fusion–bridge (BFB) cycles

What are breakage–fusion–bridge cycles?

• Cycles where unprotected chromosomes fuse, form dicentric chromosomes, create anaphase bridges, and undergo repeated breakage

• Cause severe genomic instability in cancer cells

What is telomerase?

A ribonucleoprotein enzyme that extends telomeres by adding DNA repeats to chromosome ends

What are telomerase’s components?

• hTERT: reverse transcriptase subunit

• hTR (TERC): RNA template subunit

What does telomerase do?

• Adds nucleotides to the 3′ end of chromosomes

• Maintains telomere length, preventing senescence

Where is telomerase active?

• Highly active: Germline and some stem cells

• Limited or absent: Most somatic cells (→ telomere shortening)

Why is telomerase activation important in cancer?

It is essential for unlimited replicative potential and tumor cell immortality

Why target telomerase in cancer therapy?

• Most cancers depend on telomerase for continuous growth

• Inhibiting telomerase can induce crisis and death in cancer cells

List four main telomere-targeted therapeutic strategies

• hTERT inhibitors: Directly block enzyme activity (slow effect due to gradual telomere erosion)

• Template antagonists: Oligonucleotides complementary to hTR RNA (e.g., GRN163L, in clinical trials)

• Telomere disruptors (DNA): Promote G-quadruplex structures → inhibit telomerase and uncap telomeres (e.g., RHPS4, preclinical)

• Telomere disruptors (shelterin complex): Target telomere capping proteins to uncap and destabilise telomeres.

What are the outcomes of telomere-targeted strategies so far?

Mixed success, leading to development of combination approaches integrating telomerase inhibition with other treatments

How is gene therapy used against telomerase-positive cancers?

Oncolytic viruses engineered to replicate only in telomerase-expressing cells (e.g., telomelysin) selectively kill cancer cells

How is immunotherapy applied to telomerase?

• hTERT peptides are presented by MHC molecules to activate immune responses

• Leads to immune-mediated killing of telomerase-expressing tumor cells

• Used in telomerase vaccines (several in trials)

How is telomerase therapy used in combination treatments?

hTERT inhibitors like Imetelstat may be used with other therapies for enhanced effects, since telomerase inhibition alone is slow

What is the overall therapeutic significance of telomerase targeting?

• Telomerase is critical for immortal cancer cell growth

• Targeting telomerase via inhibitors, immunotherapy, or gene therapy holds significant potential, especially in combination regimens