WK1: The Tumour Microenvironment and inducing or accessing vasculature

What is the tumor microenvironment (TME)?

The cellular and structural environment around a tumor, including cancer cells, immune cells, fibroblasts, blood vessels, and extracellular matrix (ECM).

Name four cell types found in the TME.

Cancer cells, cancer stem cells (CSCs), immune cells (e.g., T cells, macrophages), fibroblasts, endothelial cells

What is the extracellular matrix (ECM)?

The non-cellular scaffolding of proteins and carbohydrates that provides structural support and signaling cues in tissues0

What are cancer stem cells (CSCs)?

A small subpopulation of tumor cells with stem-like properties: self-renewal, differentiation capacity, and therapy resistance.

How do CSCs differ from normal stem cells?

CSCs have uncontrolled proliferation, are tumorigenic, and are often therapy-resistant.

What are common markers for CSCs?

CD133, CD44, ALDH (aldehyde dehydrogenase), OCT4.

Why are CSCs important in cancer therapy?

They are thought to drive tumor growth, recurrence, and metastasis, and are often resistant to chemotherapy and radiation.

What signaling pathways are often active in CSCs?

Wnt/β-catenin, Notch, Hedgehog.

What is hypoxia?

A condition of low oxygen concentration in tissues.

Why do tumors have hypoxic regions?

Because tumor blood vessels are disorganized and inefficient, leading to poor oxygen delivery to areas distant from vessels.

What transcription factor is activated by hypoxia?

HIF-1α (Hypoxia-Inducible Factor 1-alpha).

What does HIF-1α do?

It upregulates genes involved in angiogenesis, glycolysis, and cell survival to adapt to low oxygen.

How does hypoxia affect chemotherapy and radiation?

Hypoxic cells are often resistant to both because radiation requires oxygen to generate DNA-damaging free radicals, and many chemo drugs rely on active cell division.

What is pimonidazole used for?

It is a hypoxia marker that binds to thiol groups in proteins under low oxygen, used in research to visualize hypoxic areas.

What is angiogenesis?

The formation of new blood vessels from pre-existing ones.

Why do tumors need angiogenesis?

To supply oxygen and nutrients, remove waste, and support growth beyond 1–2 mm in size.

What is the "angiogenic switch"?

The shift in balance from anti-angiogenic to pro-angiogenic signaling, enabling tumor blood vessel growth.

Name three pro-angiogenic factors.

VEGF (Vascular Endothelial Growth Factor), FGF (Fibroblast Growth Factor), PDGF (Platelet-Derived Growth Factor).

What is VEGF and why is it important?

VEGF is the primary growth factor that stimulates endothelial cell proliferation and new blood vessel formation.

How does tumor vasculature differ from normal vasculature?

Tumor vessels are disorganized, leaky, dilated, and lack hierarchical branching, leading to irregular blood flow.

What are the consequences of abnormal tumor blood vessels?

Poor and uneven drug delivery, hypoxia, increased interstitial pressure, and facilitated metastasis.

How does abnormal vasculature affect chemotherapy?

It leads to heterogeneous drug distribution, reducing efficacy and creating sanctuaries where cancer cells survive.

What are some limitations of anti-angiogenic therapy?

Tumors can develop resistance, become more invasive, or upregulate alternative pro-angiogenic pathways.

What are HIF-1α inhibitors?

Drugs designed to block the hypoxia-inducible factor, disrupting tumor adaptation to low oxygen.

How can CSCs be targeted therapeutically?

By inhibiting their specific markers (e.g., anti-CD44), signaling pathways (Wnt/Notch inhibitors), or drug efflux pumps (MDR1 inhibitors).

Why is targeting CSCs challenging?

They are rare, heterogeneous, and have multiple resistance mechanisms

How does angiogenesis relate to sustaining proliferative signaling?

Angiogenesis provides nutrients and oxygen that allow cancer cells to continue proliferating.

How does hypoxia relate to resisting cell death?

Hypoxia can induce anti-apoptotic proteins and promote cell survival.

How does the TME influence metastasis?

The TME facilitates invasion, intravasation into blood vessels, and establishment of metastatic niches.