Progress and Perspective of Organoid Technology in Breast Cancer Research
Breast cancer, a malignant tumor with a high incidence in women, has long been a significant focus of medical research. Despite advancements in understanding and treating the disease, there remains a critical need for in vitro research models that accurately represent the biological functions of breast tumors in vivo. Traditional models, such as two-dimensional (2D) cell cultures and patient-derived xenografts (PDX), have limitations that hinder their ability to fully replicate the complexity of human tumors. In recent years, organoid technology has emerged as a promising tool, offering unique advantages over conventional methods. This review explores the progress and potential of organoid technology in breast cancer research, highlighting its merits, limitations, and future directions.
Introduction
Breast cancer has surpassed lung cancer as the most common malignancy worldwide since 2020, and it remains one of the leading causes of death among women. In China, the incidence of breast cancer has been increasing annually, with affected women tending to be younger than their Western counterparts. The disease is most common among women in their 40s and 50s, with an average age of 48–49 years, more than a decade younger than in Western countries. The diversity of mutated genes and individual differences among patients contribute to the complexity of breast cancer treatment. Despite the use of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) as markers for typing and guiding treatment, hundreds of genes are associated with breast cancer, making it challenging to develop effective therapies. The pathogenesis of breast cancer is not fully understood, and the risk factors influencing its occurrence are varied. Consequently, the development of accurate and personalized treatments has become a critical area of research.
Limitations of Traditional Biological Models
The selection of an appropriate biological model is fundamental to studying the pathogenesis of breast cancer. Traditional models include 2D cell cultures, PDX models, and organotypic tissue slice cultures (OTSCs). Each of these models has its strengths and weaknesses.
2D Cell Culture Models: The 2D cell culture model involves growing cells on a flat surface, such as a petri dish. This model has been widely used in biological research due to its simplicity, low cost, and ease of operation. However, 2D cultures fail to replicate the three-dimensional (3D) structure and microenvironment of tumors, leading to results that often differ from in vivo and clinical studies. For example, tumor cells in 2D cultures grow faster and exhibit greater variability than those in human tumors. Additionally, the lack of immunosuppression in 2D models can lead to discrepancies in drug efficacy, with many drugs showing promise in 2D cultures but failing in clinical trials.
PDX Models: PDX models involve transplanting patient-derived tumor cells or tissues into immunodeficient mice, allowing the tumors to grow in a more natural environment. PDX models preserve the biological and molecular characteristics of patient tumors better than 2D cultures, making them valuable for studying cancer metastasis and drug screening. However, PDX models are expensive, time-consuming, and lack the immune system, which is crucial for understanding tumor immune responses.
OTSC Models: OTSCs are tissue slices prepared from solid organs using a tissue microtome. These slices preserve the viability and cellular interactions of the original tissue, making them useful for studying tumor biology. However, OTSCs cannot be cultured for extended periods, limiting their use in long-term studies. Additionally, the diversity of cell types in tissue slices makes it challenging to find a suitable culture medium that supports all cell types.
The Emergence of Organoid Technology
Organoid technology has emerged as a promising alternative to traditional models. Organoids are 3D structures derived from stem cells or organ progenitor cells that self-organize to replicate the structure and function of organs. These models offer several advantages over traditional methods, including the ability to mimic the 3D architecture of tumors, maintain genetic and histological characteristics, and be derived from patient tissues. Organoids can be cryopreserved to create biobanks, enabling large-scale studies and high-throughput drug screening.
Breast cancer organoids, in particular, have shown great potential in precision medicine and drug research. They can be derived from embryonic stem cells, induced pluripotent stem cells (iPSCs), or directly from tumor cells. Organoids derived from tumor cells retain the genetic and histological characteristics of the original tumor, making them valuable for studying tumor heterogeneity and drug responses.
Comparison of Organoids with Traditional Models
Organoid models combine the advantages of 2D cell cultures and PDX models while addressing some of their limitations. Unlike 2D cultures, organoids replicate the 3D structure of tumors, including cell-cell and cell-matrix interactions. Compared to PDX models, organoids are less expensive, faster to construct, and can be genetically modified more easily. However, organoids also have limitations. They often resemble fetal tissue rather than adult tissue, and they lack vasculature and immune systems, which are crucial for studying tumor biology.
To overcome these limitations, researchers have integrated new technologies into organoid construction. For example, genetic engineering techniques, such as CRISPR/Cas9, have been used to modify organoids to study specific gene mutations and their effects on tumor behavior. Microfluidic chip technology has been employed to simulate the vascular system and control the flow of nutrients and hormones within organoids. These advancements have expanded the applications of organoids in breast cancer research.
Development of Organoid Models
The concept of organoids dates back to the early 20th century, with the first experiments on in vitro regeneration of tissues. Over the past century, significant progress has been made in organoid technology, culminating in the development of organoids from various organs, including the breast. The first breast cancer organoid model was established in 2011, and since then, researchers have developed organoids from different cell sources, including stem cells, normal breast cells, and tumor cells.
Breast Organoids from Stem Cells: Stem cells, including embryonic stem cells, iPSCs, and adult stem cells, have been used to generate breast organoids. iPSCs, in particular, have shown great potential in organoid research due to their ability to differentiate into any cell type. In 2017, researchers successfully generated human mammary organoids from iPSCs, providing a model for studying normal breast development and disease.
Organoids from Normal Breast Cells: Normal breast epithelial cells have been used to create organoids that replicate the structure and function of the mammary gland. These models have been used to study the effects of hormones and growth factors on breast tissue.
Organoids from Breast Tumor Cells: Tumor-derived organoids have been used to study breast cancer biology and drug responses. These organoids retain the genetic and histological characteristics of the original tumor, making them valuable for personalized medicine. Researchers have established biobanks of breast cancer organoids, enabling large-scale studies and drug screening.
New Techniques in Breast Organoid Construction
The integration of new technologies has expanded the applications of organoids in breast cancer research. Genetic engineering techniques, such as CRISPR/Cas9, have been used to modify organoids to study specific gene mutations and their effects on tumor behavior. For example, researchers have used CRISPR/Cas9 to knock out tumor suppressor genes in breast cancer organoids, providing insights into the molecular mechanisms of specific breast cancer subtypes.
Microfluidic chip technology has been employed to simulate the vascular system and control the flow of nutrients and hormones within organoids. This technology has been used to create lung cancer organ-on-a-chip models that replicate the clinical efficacy of drugs, demonstrating the potential of organ-on-a-chip models in drug testing. In breast cancer research, microfluidic chips have been used to simulate the influence of hormones on mammary glands and to control the shape and structure of organoids.
Applications of Breast Organoids
Construction of Breast Organoid Biobanks: Organoid biobanks have been established to preserve and study breast cancer organoids. These biobanks enable large-scale studies and high-throughput drug screening, providing valuable resources for breast cancer research.
Application of Breast Organoids in Drug Testing: Organoids have been used to test the safety and efficacy of drugs in breast cancer research. Organoids derived from patient tumors have shown similar drug sensitivity to the original tumors, making them valuable for predicting patient responses to treatment.
Application of Breast Organoids in Precision Medicine: Organoids have been used to develop personalized treatment plans for breast cancer patients. By testing drugs on organoids derived from patient tumors, researchers can predict the efficacy of treatments and optimize therapeutic strategies.
Challenges and Future Directions
Despite the significant progress in organoid technology, several challenges remain. Organoids often resemble fetal tissue rather than adult tissue, and they lack vasculature and immune systems, which are crucial for studying tumor biology. To address these limitations, researchers are exploring new techniques, such as genetic engineering and microfluidic chip technology, to enhance the functionality of organoids.
The lack of standardized protocols for organoid construction is another challenge. The reproducibility of organoid experiments can vary, making it difficult to compare results across studies. To address this issue, researchers are working to develop standardized protocols for organoid culture and characterization.
In the future, the integration of organoid technology with other emerging technologies, such as artificial intelligence and machine learning, could further enhance its applications in breast cancer research. These technologies could be used to analyze large datasets generated from organoid studies, providing new insights into breast cancer biology and treatment.
Conclusion
Organoid technology has emerged as a powerful tool in breast cancer research, offering unique advantages over traditional models. Organoids replicate the 3D structure and function of tumors, making them valuable for studying tumor biology, drug responses, and personalized medicine. The integration of new technologies, such as genetic engineering and microfluidic chips, has expanded the applications of organoids in breast cancer research. Despite the challenges, organoid technology holds great promise for advancing our understanding of breast cancer and developing more effective treatments.
doi.org/10.1097/CM9.0000000000002889
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