Hallmarks of Cancer

6 Hallmarks of cancer

Self-sufficiency in growth signals

Evading apoptosis

Insensitivity to growth signals

Tissue Invasion and metastasis

Limitless replicative potential

Sustained angiogenesis

Self sufficiency in growth signals hallmark

Sustaining proliferative signal

Cancer cells do not require normal growth signals to continue division or make their own causing autocrine signaling feedback loop

3 disruptions of growth signals

3 disruptions of growth signals

Alterations in extracellular growth signals (PDGF, EGF)

Alterations of transcellular transducers (RAS)

Alterations of intracellular circuits that translate those signals into action

What is autocrine signaling

positive feedback loop of cancer cells making their own growth factors

self sufficiency in growth factor hallmark

Insensitivity to anti-growth signal hallmark

NF2 gene- encodes Merlin tumor suppressor that regulates contact inhibition

NF2 inactivation causes cancer in nervous system

What is contact inhibition?

Dense populations of normal cells suppress proliferation

Things involved with evading apoptosis hallmark

p53

Caspases

PI3K kinase AKT pathway

IFG1/2 and IL-3

p53 role in apoptosis

Transcription factor- upregulate pro-apoptotic genes

Caspases role in apoptosis

family of intracellular proteases that destroy cell

PI3K kinase-AKT pathway role in apoptosis

transmit anti-apoptotic signals

IFG1/2 and IL-3 role in apoptosis

External survival factors

Limitless replicative potential hallmark

DNA ends don’t replicate bc telomeres

Less telomerase in cancer cells, become immortal

Sustained angiogenesis hallmark

New blood vessels formed

Vascular endothelial growth factor (VEGF) grows tumor cells

Tissue invasion metastasis hallmark

tissue invasion- release of secreted proteases which change ECM to make space for cancer cells

2 types of tissue invasion

some tumors make their own proteases

others co-opt stromal cells to induce protease release

Metastasis

tumor cells breaking away from primary tumor and making a secondary tumor

Several discrete steps in the biological cascade of metastasis

Loss of cellular adhesion

Increased motility and invasiveness

Entry and survival in the circulation

Exit into new tissue

Colonization of a distant site

Extracellular matrix (ECM)

network of proteins that support and give structure to cells and tissues

helps cells attach to nea

rby cells

important for cell growth and movement

Functions of ECM

Adhesive substrate

Provides structure

Presents growth factors to their receptors

Sequesters and stores growth factors

Senses and transduces mechanical signals

Stroma

Cells and tissues that support and give structure to organs and glands

made of connective tissues, blood vessels, lymphatic vessels, and nerves

provides nutrients to tissue/organ and removes waste

Cell adhesion proteins

Cells adhere to each other and ECM through cell adhesion molecules (CAMs)

Cadherins linked to the actin cytoskeleton by catenins

Selectins mediate transient cell-cell adhesions in the bloodstream

N-CAM contribute to fine-tuning of adhesive interactions

what is intravasation

invasion into vessels

what happens when carcinoma cells get into stromal compartment?

get access to blood and lymphatic vessels

triad of carcinoma cells, macrophages, and endothelial

cells enables cancer cells to invade capillaries

Post intravasation CTCs

once in blood/lymphatic vessel circulating tumor cells (CTCs) can travel to other areas

blood is hostile, CTCs attach to platelets to survive

small portion of CTCs are successful

Extravasation

when cancer cells escape from lumina of vessels and penetrate into surrounding tissue

tumor cell colonization

newly metastasizing cancer cells may form micrometastases which can expand into clinically detectable masses

growth of microscopic to macroscopic metastases is called

Colonization

what step of invasion does colonization represent?

metastasis cascade

metastatic inefficiency

low success rate of cancer cell successfully completing all invasion metastasis steps

rate limiting determinant of invasion metastasis:

colonization bc it’s most complicated step

what is Epithelial-mesenchymal transition (EMT)

carcinoma cells going from epithelial to more mesenchymal to acquire motility and invasiveness

how does EMT work

expression of epithelial hallmarks E-cadherin and cytokeratins are repressed

expression of vimentin and fibronectin and N-cadherin are induced

EMT and transcription factors

EMT programmed by transcription factors

seed and soil hypothesis

metastasis broken into 2 major phases:

physical dissemination of cancer cells from the primary tumor

adaptation of these cells to foreign tissue microenvironments that result in successful colonization

which is seed and which is soil

preference patterns of tumor metastasis are the product of favorable interactions between metastatic tumor cells (seed) and their organ microenvironment (the soil)

why do tumors in some places have a high probability of metastasis and other tissues don’t?

seed and soil hypothesis and layout of vessels dictate metastasis

4 emerging hallmarks of cancer

Avoiding immune destruction

Tumor-promoting inflammation

Genome instability and mutations

Deregulating cellular energetics