The role of cancer stem cells in maintaining and spreading a tumour has remained a hypothesis until recently. Now, a group of researchers from Cancer Institute (WIA), Chennai, have shown that in a common type of ovarian cancer, cancer stem cells can morph into special cell types that build tiny bunches of blood vessel within the tumour.
Further, the team also found that cells making up lymph vessels, another essential component of the tumour which aids in spreading the tumour (metastasis), can be made by the cancer stem cells. The study also indicates that a certain factor — vascular endothelial growth factor (VEGF) — could be responsible for this morphing (trans-differentiation) of the stem cells. The study was published in the journal Angiogenesis.
Epithelial ovarian cancers are about 85% of all ovarian cancers. And the researchers studied the most common epithelial ovarian cancer subtype — high-grade serous adenocarcinoma of the ovary.
Targeting stem cells
Cancer stem cells are small in number in the tumour but are perhaps the most difficult ones to target as they resist chemotherapy and radiation. They are also responsible for the relapse of cancer. Hence, there is immense interest in studying these types of cell and how they can be targeted for management of cancer.
Blood vessels are tubes lined on their inner sides by endothelial cells and on the outer by pericytes. The walls of a lymph vessel, which transports fluids through the body, are only lined by endothelial cells.
“The origin of components of a blood vessel — endothelial cells and pericytes — in primary malignant cells from ovarian tumours has been established in our study. Up to 20% of the blood vessels in the tumours were derived from the cancer stem cells,” says Prof. T.S. Ganesan, from Cancer Institute (WIA), Chennai, who led the study. “This is the first study to make this connection between lymphatic endothelial cells and the stem cells,” he adds.
Tracing mutation
The researchers established the connection in several steps. The first indicator was the proximity of the cancer stem cells and the blood vessels. Secondly, specific genetic mutations observed in the stem cells were also present in the endothelial cells.
When cancer stem cells are grown in the lab (in vitro) in a three-dimensional matrix, they form spherical structures referred to as spheroids. The cancer stem cells when grown under specific conditions are seen to develop into endothelial cells, pericytes and lymphatic endothelial cells.
“We found that the cells grown under specific conditions showed functional features of normal blood vessels such as formation of tubes,” said S. Krishna Priya, first author of the study, in an email. “We also identified a growth factor (VEGF), which is already known to play a major role in the growth of blood vessels. This is also important for cancer stem cells becoming endothelial cells,” she explained.
The spheroids were labelled with green fluorescent protein and injected into mice. “Since the spheroids were labelled, the tumours formed by these cells would glow green and hence, the blood vessels too. We found that the blood vessels and lymphatic vessels in mouse tumours showed the green fluorescence, suggesting that they are derived from cancer stem cells,” says Ms Krishna Priya.
The study has implications for management of cancer because a tumour needs supply of both blood and lymph to grow and spread. So targeting the cancer stem cells can curtail both. The study also suggests that drugs that inhibit the growth factor may be more effective clinically.
