Vasculature of normal and tumor tissues
Red blood cells bring oxygen to cells through a network of blood vessels. Lack of oxygen (hypoxia) is the most aggressive stress for our body, which must be able to respond in a few seconds. If the stress persists, cells die.
The formation of the vessels is a process called angiogenesis. During embryonic development, this complex process requires a spatial and temporal coordination of several cell types, each producing many kinds of factors. These factors are proteins that either stimulate or inhibitangiogenesis. In the adult, they are in equilibrium, producing a state of ‘dynamic rest’ that is activated in case of wound healing.
When tumour cells multiply, those in the tumor center, far from blood vessels, are in hypoxia. The concentration of both pro- and anti-angiogenic factors is increased in tumors, but the balance is in favor of the latter, which triggers angiogenesis and allows tumor development. The tumor vasculature is very flawed: there are no arteries or veins, but only undifferentiated vessels, poorly functional, bringing low oxygen supply. This network is in perpetual reworking, whereas normal tissues are stable. A tumor can be described as a wound that never repair. Despite a higher blood vessel density than in normal tissues, cancer cells are therefore frequently in hypoxic condition.
Immune cells (shown in green in the figure) and antibodies, which defend our body from external agressions and cancer cells, are transported by the blood flow in all of our tissues. Poor vascularization of tumours, but also the production by tumor cells of factors that repress the immune system, lead to a sharp decline in immune surveillance in tumors, facilitating their growth.
The study of tumor angiogenesis has raised the idea that deprivation of blood vessels should suffocate cancers and make them regress without affecting normal tissue where angiogenesis is little active. This led to the development of a new class of drugs, known as anti-angiogenic, which prevent the establishment and replacement of the tumor vasculature.
Anti-angiogenic therapies are designed to increase hypoxia. In the center of the tumor, the cancer cells deprived of oxygen die, creating areas of necrosis and sometimes a decrease of the volume of the tumor.
Resistance to anti-angiogenic treatments
This new class of molecules raised high expectations, that were only partly only fullfiled. Indeed, if they significantly improve the quality of life of patients and delay the progression of the disease, in the majority of cancers they only marginally prolong life, and their side effects (hypertension, bleeding) limit their use.
Analysis of the causes of this relative failure highlighted the key and complex role of hypoxia that induces tumor necrosis but also has adverse effects:
- The decrease of vascularization reduces the penetration of anti-cancer drugs and the effectiveness of radiation therapy that requires the presence of oxygen.
- Hypoxia activates in cancer cells the synthesis of proteins that foster their migration, allowing them to invade the surrounding tissue or colonize distant tissues. In patients, this mechanism has been particularly observed in glioblastoma, a form of brain cancer.
Normalization of tumor vascularization
At first, anti-angiogenic treatments transiently re-equilibrate the angiogenic balance, eliminate less functional tumor vessels, which reduces intratumoral hypoxia. There is a transient improvement of the immune response of the host against the tumor.
However, continuation of the anti-angiogenic treatment strongly increases hypoxia in tumors, which induces necrosis but also stimulates the migration of cancer cells that escaped treatment. Rather than creating and maintaining a prolonged hypoxic environment in tumors, the strategy now advocated by many experts is to normalize the tumor vasculature in a sustainable way to reduce hypoxia, cell migration and improve drug delivery and radiotherapy.
SXL05: a therapeutic strategy of rupture
SeleXel develops a siRNA, SXL05, whose target is overexpressed in prostate cancer relapsing after surgery as compared to not relapsing tumors and in agressive breast cancers. Treatment of experimental tumors by SXL05 increases the vascular density, reduces hypoxia and the growth of prostate tumors and metastasis of breast tumors.