Page 156 - Concise Pathology for Exam Preparation ( PDFDrive )

6 Neoplasia 141

• Angiogenesis is required not only for tumour growth, but also for metastasis. Without
access to the vasculature, the tumour cells cannot spread to distant sites.
• Sprouting of new vessels from already-existing ones is called neoangiogenesis; whereas,
vasculogenesis occurs by recruitment of endothelial cell precursors. Tumour blood
vessels differ from the normal vasculature by being leaky and unorganized.
• The pro-angiogenic factors are produced by tumour cells or derived from inflammatory
cells (eg, macrophages) that infiltrate tumours. Hypoxia activates transcription factor
Hypoxia-inducible factor (HIF)-1a which in turn activates pro-angiogenic factors like
VEGF and bFGF. Other promoters of angiogenesis include angiopoietins 1 and 2. In-
hibitors of VEGF are being used for the treatment of advanced cancers. These are not
curative but can prolong survival.
• Under normal circumstances, p53 increases expression of anti-angiogenic factors like thrombo-
spondin-1, angiostatin, tumstatin and endostatin. Loss of p53, therefore, allows angiogenesis.

Q. Describe the mechanism and biology of invasion and metastasis.
Ans. In the early stage of tumourigenesis, the cells are not invasive and metastatic. Progres-
sive genetic aberrations are associated with the appearance of new clones with invasiveness
and metastatic ability. Highly metastatic cells often acquire alterations in more genes than
nonmetastatic cells. Potentially important genes associated with epithelial metastasis include
twist-related protein (TWIST) and the zinc-finger group gene SNAIL; these genes encode
transcription factors which increase epithelial-mesenchymal interactions. The following
are the steps involved in invasion and metastasis (Flowchart 6.6; Fig. 6.5):

Development of a rapidly proliferating clone of cancer cells

Emergence of a subpopulation of tumour cells with the
biological characteristics essential for metastases

Adhesion to and invasion of basement membrane by tumour cells
Tumour cell–ECM interactions and degradation of ECM due to:
• ↑ Metalloproteinase expression on tumour cells
• ↑ Proteases (MMPs, cathepsin D, urokinase
plasminogen activator)
• ↓ Tissue inhibitors of metalloproteinases (TIMPs)
Cleavage of basement membrane proteins collagen
laminin by MMP2 and MMP9
Invasion of ECM

Development of leaky blood vessels with endothelial
gaps having direct contact with cancer cells

Intravasation (entry into vessels) by tumour cells

Interaction with host lymphoid cells to form tumour cell emboli

Adhesion to basement membrane of vessel wall

Extravasation at a distant site

Metastatic deposit

Proliferation as a secondary colony aided by
angiopoietins 1 and 2
FLOWCHART 6.6. Sequence of events in invasion and metastasis.

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