The Role of Angiogenesis in Cancer
In early phases of solid tumour formation, tumour tissues are thin, have small cell populations and tend to be poorly vascularized (2). In most tumour cell types, the tumour can grow to around 1-2mm in diameter before requiring vascularization for continued growth (3). A tumour's dependence on angiogenesis is likely due to a demand for oxygen, nutrients, growth factors, proteolytic enzymes and other essential material (3,4), as well as the need to remove carbon dioxide and other metabolic wastes (5). Angiogenesis inhibitors that are not cytostatic when tested in vitro, often appear to inhibit tumour growth in in vivo models (2). Tumor angiogenesis (Figure 7.3.1) occurs when malignant tumor cells release molecules into the surrounding normal host tissue; through signaling pathways these molecules can activate factors that encourage blood vessel growth.
The continuous growth of tumour results in the creation of hypoxic pockets due to the lack of proper penetration of oxygen-carrying vessels; hypoxia, along with hypoglycemia and mechanical stress, is a major stimulus for tumour angiogenesis (4,6). Vascular endothelial growth factor (VEGF), induced by hypoxia, has been shown to be central to a tumor's ability to undergo angiogenesis and the regulation of angiogenic events (10). VEGF will be discussed in further detail in Section 4 of this chapter. It has been postulated that some subsets of tumour tissues actually upregulate anti-angiogenesis signals in order to maintain the hypoxic conditions (5).
Neovascularization also plays a role in promoting metastasis. Tumors can shed tumor cells into adjacent blood vessels and enter the systemic circulatory system to metastasize (3). Newly formed vessels are more permeable than mature vessels, allowing easier penetration into the circulatory system (3). Highly vascularized tissue allows for circulating tumor cells to enter target tissues via capillary beds (9). Furthermore, upon reestablishment into the target tissue, tumours may lie dormant until a subsequent angiogenic switch is activated for enhanced growth and further metastatic potential, resulting in repetitive cycles of this process (9).
Some cancers, such as pancreatic ductal adenocarcinomas, do not rely on angiogenesis for growth (2,5).
Tumour angiogenesis is usually due to an imbalance in pro- and anti-angiogenesis signals, refered to as the angiogenic switch (6). New vessels created via tumour angiogenesis tend to lack branching organization, and are often irregularly shaped, with uneven diameters, and imperfect lining of epithelial cells (Figure 7.3.2). (4,6). As a result of these changes as well as vascular basement membrane deficiencies, vessels tend to be convoluted and are subject to erratic blood flow, microhemorrhaging, leakiness, and abnormal levels of epithelial cell proliferation and apoptosis (5,6). It has long been thought that pericytes are missing from tumour blood vessels, but recent studies have shown that pericytes are loosely associated with most neovasculatures, and may play a key role in maintaining functional tumour blood vessels (5). Due to constant remodelling, similar tumours and even their metastases have different levels of blood flow and permeability (7).
Although alterations in blood vessel formation are most often spoken of in cancer, similar changes occur within lymphatic vessels (8). Angiogenesis can induce the formation of lymphatic vessels and the spread of cancer cells to regional lymph nodes while attracting immune and inflammatory cells (11). Commonly, lymphatics are absent within tumours, possibly as a result of lymphatic channels being physically compressed by the dense tumour cell mass (8). This may impede the delivery of chemotherapeutic agents (7). Strangely, peripheral lymphatic vessels are enlarged due an excess of local VEGF-C (8). These new englarged vessels can then collect cancerous cells from the tumour's surface along with the interstitial fluid and promote metastasis (8).
1. Ferrara, N. & Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967-974.
2. Folkman, J. (1990). What Is the Evidence That Tumors Are Angiogenesis Dependent? Journal of the National Cancer Institute 82, 4-6.
3. Matsuda, Y., Hagio, M. and Ishiwata, T. (2013). Nestin: A novel angiogenesis marker and possible target for tumor angiogenesis. World Journal of Gastroenterology 19, 42-48.
4. Ribatti, D. (2011). Novel angiogenesis inhibitors: Addresssing the issue of redundancy in the angiogenic signaling pathway. Cancer Treatment Reviews 37, 344-352.
5. Hanahan, D. and Weinberg, R.A. (2011). Hallmarks of Cancer: The Next Generation. Cell 144, 646-674.
6. Sund, M., Xie, L., and Kalluri, R. (2004). The contribution of vascular basement membranes and extracellular matrix to the mechanics of tumor angiogenesis. Apmis 112(7‐8), 450-462.
7. Jain, R.K. (2003). Molecular regulation of vessel maturation. Nature Medicine 9, 685-693.
8. Carmeliet, P. and Jain, R. K. (2000). Angiogenesis in cancer and other diseases. NATURE-LONDON-, 249-257.
9. Zetter, B. R. Angiogenesis and tumor metastasis. (1998). Annual review of medicine 49(1), 407-424.
10. Rahimi, N. The Ubiquitin-Proteasome System Meets Angiogenesis. (2012). Molecular Cancer Therapeutics 11(3), 538-548.
11. Marmé, D., & Fusenig, N. E. (2008). Tumor angiogenesis basic mechanisms and cancer therapy. Berlin: Springer.