Hallmark No.

5: Sustained angiogenesis/ neovascularization

Angiogenesis is the formation of new blood vessels from existing ones. It involves sprouting, splitting,
remodeling of existing vessels. In normal condition when a multicellular organism is growing, cells induce
angiogenesis to recruit new blood supply. Hypoxia is still persistent in tumor cells because rapidly
proliferating tumor cells outgrow capacity of host vasculature, therefore they require additional
vasculature to supply energy and nutrients for continued growth. It switches on the angiogenic switch to
allow it to directly and indirectly influence blood supply it is receiving.

Regulation of angiogenesis is dependent on angiogenic inducer and inhibitor balance. An increase or

decrease tips balance of “angiogenic switch”.Among the inducers and inhibitors, Vascular
Endothelial growth factor- A (VEGF- A) and thrombospondin- 1 have been widely studied in
neoplastic vascularization.

VEGF- A exhibits its angiogenic effect by inducing

Source: The Role of Anti-Angiogenic
Agents (VEGF)
expression of α1β1, α2β1 and αvβ3-integrins. It affects
endothelial cells that line the blood vessels in many ways :
proteolytic activity ,endothelial cell proliferation and
migration, and stimulating microvascular leakage – all of
them promoting angiogenesis.VGEF can reach receptors
on the endothelial cells of blood vessels that surround the
tumor, resulting to stimulation of angiogenic signal in blood
vessel. Newly formed endothelial cells organize into hollow
tubes and create new basement for vascular
stability.VEGF regulates inhibitors or apoptosis to help
new endothelial cells to survive VEGF activates
endothelial cells to express necessary proteins to allow
formation of new blood vessel

NEW BLOOD VESSEL = FACILITATE TUMOR

GROWTH

Pericytes are important components of the tumor neovasculature. Pericytes provide mechanical and
physiologic support to endothelial cells and secrete Platelet Derived Growth Factor (PGDF) which helps
in pericyte and smooth muscle cell recruitment

A variety of bone marrow-derived cells contribute to tumor angiogenesis. These include macrophages,
neutrophils, mast cells, myeloid progenitors . These cells help trigger angiogenic switch by providing
tumor microenvironment and secrete various growth factors and protect vasculature from effects of drug
targeting endothelial cells signaling.

Hallmark No. 6: Tissue Invasion and Metastasis

Source: Winslow, T. Metastasis. In: National
Almost 80- 90 % of cancer related deaths are Cancer Institute. 2014.
caused by metastasis of cancer in which cancer
cells spread to other body parts, invade and overtake the tissues to form more tumors. Tissue invasion
involves tumor cells expanding into nearby environment while metastasis involves tumor cells breaking
away from the primary tumor and migrating to new location to establish new or secondary tumor

Metastasis is growth of tumor in new location. Cancer can spread to different parts via hematogenous
spread or through the lymphatic system

Mechanism of Metastasis

Steps of metastatic cascade include the following: local

invasion, intravasation, circulation, extravasation, and
colonization or target organs

Source: Molecular Priniciples of Metastasis: A Hallmark

of Cancer Revisited

Process of metastasis can be explained in five parts: local invasion, intravasation, circulation,
extravasation, and colonization or target organs. During the process invasion, cells detach
themselves from the original tumor and utilize extracellular proteases to break the extracellular
matrix and trigger release of growth factor that can influence growth and invasion of tumor. During
the process of intravasation, tumor cells enter the veins and lymphatic system. New vessels are
formed which allows growing tumors to access nutrients and oxygen. Primary tumor generates a
leaky neovasculature which makes it easier to access to the circulation. In cell dissemination in the
circulation, cancer cells invade and associate with non-neoplastic cells to enhance survival
rate.They also secrete cathepsin B and thrombin to facilitate platelets in aggregating around the
tumor cells. This platelet coat helps in facilitating extravasation and arrest in narrow capillary beds.

During the process of extravasation, cancer cells lodged in microvasculature to initiate growth and
formation of embolus. Once cancer cells are integrated, majority extavasate into the parenchyma
will die but some cells may become dormant and can survive for months to decades. The
disseminated tumor cells may reinitiate growth and established new tumor
 Cancer cells metastasize to specific target organs in a process called as “Metastastic
Organotropism”.
Source: Molecular principles of metastasis: a hallmark of cancer revisited

ROUTES OF METASTASIS

Cancers may spread to distant sites through:

1. Direct growth into adjacent tissues

2. Carcinomas metastasize by lymphatic route

3. Blood borne metastases usually occur in liver, lungs, kidney and adrenals

4.Transcoelomic spread

5. Spread along epithelium-lined surfaces

6. Spread via cerebrospinal fluid