Angiogenesis And Breast Angiosarcoma

Introduction

Definition of angiogenesis

Angiogenesis is the process of forming new vessels from existing blood vessels in response to the body’s demand for oxygen and nutrients, thus playing a crucial role in several physiological situations.¹ The new vessels are formed by specialised cells that line the inner of the blood vessels called endothelial cells.

Overview of breast angiosarcoma

Breast angiosarcoma is an extremely rare and aggressive tumour, accounting for only 0.05% of breast cancer cases.² These tumours originate from the uncontrollable proliferation of endothelial cells and can be divided into two subtypes based on medical history and occurrence:³ 

1. Primary breast angiosarcoma 

This type of tumour predominantly occurs in people without a history of cancer.

2. Secondary breast angiosarcoma 

This type of tumour develops in patients who have undergone breast cancer therapy including surgery and radiotherapy. There is a higher chance of the tumour developing not only in the breast but also in the arms close to the surgery site. 

Regardless of having primary or secondary angiosarcoma, patients may present with swelling, fullness, discolouration, or purplish appearance on the skin of the breasts or arms; however, rapidly growing mass is more common in the primary breast angiosarcoma while pain and multifocal rash are mostly found in the secondary breast angiosarcoma.^3,4

A study indicates the median age for primary breast angiosarcoma patients is 50-54, which is 20 years younger than the median age for secondary breast angiosarcoma patients, which is 70-74 years. The median overall survival in primary and secondary breast angiosarcoma is 93 and 32 months respectively, although several factors including age, tumour size, or treatment history can associate or affect the survival outcome.⁵

Importance of studying angiogenesis in breast angiosarcoma

Once the mass located in the breast of an angiosarcoma sarcoma patient is removed, it can then be further analysed, labelled by endothelial cell markers, and observed under a microscope. This allows us to observe an abundance of endothelial cells dominating the lesions where they should not be.^3,6,7 The endothelial cells may have abnormal shapes, larger nuclei, a lower degree of differentiation (abnormal but looks like normal cells), and may tend to form irregular structures of blood channels.^3,6,7

Studying angiogenesis can shed light on uncontrolled endothelial cell proliferation. Are there any specific factors that trigger the out-growing of endothelial cells? Because of the abnormal patterns in those endothelial cells, it is promising and worth trying to find the specific markers or molecular mechanisms of the endothelial cells to develop effective therapy against tumours.^3,6,7

Angiogenesis process

Explanation of angiogenesis and tumour growth

Angiogenesis is a tug-of-war between two groups of factors: pro-angiogenic factors and anti-angiogenic factors.⁸ Once pro-angiogenic factors pull their ropes over the boundary, endothelial cells will respond to the pro-angiogenic signal and proliferate to form new blood vessels.

Uncontrollable angiogenesis is one of the biggest barriers to curing cancer. The increased supply of oxygen and nutrients supports or accelerates tumour growth. Newly formed capillaries serve as new roads for tumour cells to travel and settle in a distant place, which is called tumour metastasis. As a result, the blood network becomes unstable and fragile, leading to irregular and uneven blood flow accompanied by the low efficacy of therapy against tumours. Furthermore, the uneven blood flow contributes to low oxygen (hypoxia) in some areas, which drives more angiogenesis within the tumour.¹ 

Key players in angiogenesis

The whole process of angiogenesis is an orchestra of multiple molecules: initiation, creating spaces for endothelial cells to move, promoting the proliferation and movement of cells, and recruiting supportive cells to maintain the blood network structure.⁹ Here are some key molecules in angiogenesis:¹

1. Vascular endothelial growth factor (VEGF) family

The VEGF protein family is the most remarkable and important molecule in angiogenesis. Every protein member has their respective roles in angiogenesis. VEGF-A is the best-known member and primarily responsible for the initiation of forming new blood vessels. Excessive production of VEGF-A by a tumour will result in excessive angiogenesis.

2. Fibroblast growth factor (FGF) family

The FGF protein family consists of several proteins such as FGF-2. They promote endothelial cell proliferation and migration by working with other pro-angiogenic factors. In some pathological angiogenesis, the resistance to anti-VEGF therapy is believed to be related to FGFs.

3. Integrins

The extracellular matrix is the wall of blood vessels between endothelial cells and surrounding tissues.¹⁰ It is made up of several types of proteins and provides support to maintain the structure of blood vessels. Integrins on the endothelial cell surface allow the cells to bind to the extracellular matrix for anchoring or moving to the next places.

4.  Matrix metalloproteinases (MMPs)

MMPs are proteases that digest extracellular matrix. In the initial stages of angiogenesis, endothelial cells will release MMPs to create spaces to migrate and form new vessels.

5.  Notch signalling pathway

There are two types of endothelial cells: tip cells sense and move toward the pro-angiogenic signal, while stalk cells follow the tip cells and form the structure of blood vessels. The balance between Notch signalling and VEGF determines which type of cell endothelial cells should differentiate into. Cells that receive high concentrations of VEGF and have low notch levels will become tip cells; cells with low VEGF and high notch levels will differentiate into stalk cells. 

6. Platelet-derived growth factor (PDGF)

PDGFs are growth factors with four members that promote the proliferation and migration of endothelial cells; they also attract supportive cells to stabilize the structure of newly formed blood vessels at the late stage of angiogenesis.

Steps of angiogenesis

Angiogenesis is a complex process; let’s unfold into the following steps:¹¹

1. Mission starts: Angiogenesis starts with endothelial cells responding to pro-angiogenic signals
2. Since the endothelial cells are located at the inner wall of blood vessels, they must break the wall to find a way out. The secreted proteases like MMPs “dissolve” the wall, paving the way for their following construction work
3. The specialised endothelial cells, and tip cells, sense the resource of pro-angiogenic signals by their tentacles, and then move toward the area, guiding the following endothelial cells to the correct construction site
4. The arrival of endothelial cells now start to proliferate rapidly, differentiate into stalk cells, and connect to each cell to form new branches out of the existing vessels. The newly formed branches are hollow, allowing the blood to flow through once the whole process is done
5. The new vessels will need extra support. Smooth muscle cells and pericytes will be summoned and cover the endothelial cells, giving the structure extra support for endothelial cells
6. Now we have healthy, strong, and solid new blood vessels. The blood flow will take red blood cells to further places for nutrient and oxygen supply

Regulation of angiogenesis

The initiation of angiogenesis is largely determined by oxygen concentration. Low levels of oxygen, which can also be referred to as hypoxia, trigger the expression of the pro-angiogenic factors that were listed above. A transcription factor, hypoxia-induced factor (HIF), maintains a low level of oxygen concentration; however, it responds to the low oxygen and accumulates to form a functional complex. The complex then binds to the genes of pro-angiogenic factors and promotes their expression.¹¹

Angiogenesis in breast angiosarcoma

Pathogenesis of breast angiosarcoma

The following factors are reported to have a correlation with breast angiosarcoma. However, it is important to be aware that the rarity of this cancer has limited comprehensive studies.¹²

1.  Genetics change

Lack or overexpression of functional molecules in endothelial cells may result in uncontrollable proliferation. The change in genes includes those regulating cell proliferation and survival, and the pro-angiogenic factors promoting the angiogenesis process. We will mention some examples in the later section. 

2. History of radiation therapy

Secondary breast angiosarcoma is strongly associated with the history of radiotherapy. Reports suggested a median of 6 to 7 years in patients who had received radiotherapy against breast cancer.^4,13 Although the detailed mechanism still needs further investigation, the genetic change in endothelial cells by radiation may play a role in the initiation and development of cancer.

3. Lymphedema

Lymphedema refers to the abnormal swelling in the body’s tissues. It is highly associated with breast angiosarcoma patients who have undergone surgery to remove their breasts and axillary lymph node dissection.^14,15 The patients initially presented with lymph swelling, followed by symptoms of secondary breast angiosarcoma include mass and purplish appearance during the time.¹⁵ 

Role of angiogenesis in breast angiosarcoma

Our body requires blood vessels to deliver oxygen and nutrients, and tumours require extra support after reaching a certain size. Targeted therapy against specific pro-angiogenic factors may be a promising choice in treating angiosarcoma. However, further investigation and research are still required. 

Molecular mechanisms involved

The rarity of angiosarcoma limits the prevalence of studies of molecular mechanisms in angiosarcoma. From clinical samples, scientists still conclude some molecular changes within tumour regions.¹⁶

1. MYC

MYC is a gene-generating MYC protein that regulates cell proliferation and survival. Scientists tend to observe high expression of MYC proteins in breast angiosarcoma patients’ samples.¹⁷ Other research also suggests that MYC protein overexpression is related to radiotherapy.¹⁶ The outgrowth of endothelial cells may contribute to the MYC protein.

2. TP53

TP53 gene encodes an important tumor suppressor protein, p53. Cells with normal TP53 will not undergo unlimited growth, while cells with a deletion or mutation in TP53 will experience uncontrolled cell growth and become tumour cells.¹⁸ Scientists are able to identify TP53 mutations in secondary breast angiosarcoma patients despite its low incidence.¹⁹ 

3. Pro-angiogenic signalling pathways

As mentioned above, any changes in the pro-angiogenic molecules or pathways may promote the unlimited and uncontrollable growth of endothelial cells,  resulting in the formation of abnormal blood vessels: overexpression of pro-angiogenic factors or consistently activated Notch signalling pathway. However, the clinical relevance between pro-angiogenic signalling pathway and pathogenesis remains unknown.²⁰

Treatment strategies

Targeting angiogenesis as therapy

Although some patients have a highly positive pro-angiogenic factor (VEGF-A) expression within the tumor region, the available evidence and research are still too insufficient to establish the correlation between their high expression and treatment outcomes.^21,22 However, ongoing clinical trials are being conducted to evaluate the responses of angiosarcoma to pro-angiogenic factor target drugs.²³

Combination therapies

There is no gold standard treatment for breast angiosarcoma patients because of the rarity⁷. The most common treatment strategies include surgery to remove the tumor, radiotherapy, and chemotherapy to eliminate the tumor cells. Doctors may consider combining therapy methods to improve the treatment outcome due to the rapid growth of tumours and to prevent reoccurrence.²⁴

Surgery followed by adjuvant radiotherapy is the optimal treatment for patients. One review article suggests radiotherapy combined with surgery is helpful for tumour control.²⁵ Some patients also have good responses after surgery and chemotherapy treatment.^26,27.

Challenges and future directions

Patients who undergo surgery and radiotherapy to remove the lesion have a high recurrence rate of approximately 50%.^3,7 The true vascular lesion may be too deep or too small to be discovered. It is suggested to remove all irradiated skin or do a deep analysis to confirm the range of abnormal cells before surgery.^28,29

When it comes to treatment, concerns about using radiotherapy persist. Given that radiotherapy is one of the leading causes of secondary breast angiosarcoma, the question arises: is it a good choice?⁷ Chemotherapy studies in angiosarcoma patients are either case reports or contain small groups; moreover, patients may have resistance against a specific drug.²⁷ 

Large-scale and comprehensive studies are required to understand the mechanisms for breast angiosarcoma and to help improve treatment strategies. Combination therapy may include drugs that target multiple pathways; patients may have a diagnosis at an early stage to receive effective treatment; or scientists could conclude more risk factors to prevent or monitor breast angiosarcoma.

Summary

Breast angiosarcoma is a rare type of cancer that originates from endothelial cells growing uncontrollably. Angiogenesis is believed to be involved in the development of cancer since patients have accumulated endothelial cells and increased pro-angiogenic factors within the tumour region. The limited available cases and studies result in a lack of comprehensive understanding and standard treatments. The most common therapies include surgery, radiotherapy, and chemotherapy. However, patients who receive either one of them or the combination therapies, still experience a high rate of recurrence and low overall survival. Scientists are studying the mechanisms and exploring the drugs against multiple signalling pathways to improve the therapy efficacy and clinical outcome.