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Research progress of breast cancer based organ chip platform in Pharmacology&Therapeutics
2022-07-15 884

In terms of simulating tissue heterogeneity and reproducing pathological microenvironment,The organ chipmodel has obvious advantages over traditional in vivo and in vitro models, and is expected to provide an effective method for screening anti breast cancer drugs.


The incidence rate of breast cancer is the highest among all the cancers suffered by women in the world. breast cancer usually originates from the excessive proliferation of epithelial cells in ducts or lobules, and initially develops into benign tumors. The pathological process of breast cancer originating from ducts is that normal epithelium transforms into atypical flat epithelium, and then forms atypical ductal hyperplasia, and then progresses to ductal carcinoma in situ, eventually leading to invasive ductal cancer and malignant breast cancer. On the other hand, lobular breast cancer originates from positive ductal carcinoma Frequent lobular epithelial cells develop into atypical lobular hyperplasia, which then progresses to lobular carcinoma in situ and then to more aggressive invasive lobular carcinoma. Another rare type of breast tumor, accounting for less than 1% of breast malignancies, is breast sarcoma caused by heterogeneity. In addition to hemangiomas, lipomas and neuromas in the breast are also common. The pathogenic factors of breast cancer include hormone, age, gene mutation, DNA repair system failure, chemical and environmental carcinogen, diet and lifestyle. Although breast cancer has shown a high cure rate, recurrence and drug resistance cases occur from time to time. In order to deeply understand the molecular mechanism of breast cancer occurrence and development, it is necessary to build an innovative model to study breast cancer


Organ chipis a new technology for building in vitro models. It combines microfluidics and tissue culture methods to build organ physiological microsystems on the chip, including key elements of organ microenvironment such as tissue interface, biological fluid, mechanical force, etc. Among them, mechanical force and fluid are key factors for tissue development and morphological maintenance. Cells convert mechanical signals and mechanical signals into biochemical signals guiding important cell functions.


Reproducing the heterogeneity of breast cancer


Based on the demand for complex tumor cell research, breast cancerThe organ chipplatform has been developed to restore the process of breast cancer disease progression. In order to reshape the heterogeneity of breast cancer, a variety of related cells have been included, and the richness of the model has been further improved. The participation of T cells has further explored the pathological mechanism of breast cancer, and the reasons for the heterogeneity have also been partially explained.


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Image 2 The organ chip model of breast cancer based on matrix remodeling constructed by Gioiella [1] and others


remodel the process of metastasis


death induced by breast cancer is mostly the result of cancer metastasis to other parts. Cancer metastasis is a complex pathophysiological process, which depends on the interaction between the components of the tumor microenvironment and the cancer cells themselves. Recent studies have shown that the main target organs of breast cancer metastasis are lung, liver, bone, brain and lymph nodes. Bersini et al. [2] used a 3D based chip model to monitor the migration of cell migration across endothelial cells and breast cancer into bone. The model was composed of gel channels containing bone differentiation, and hBM-MSC bone derived cells seeded in matrix gel formed bone channels. Endothelial cells were seeded into a central medium channel to produce monolayers, and breast cancer cells flowed into the same channel

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Figure 3 The tubular model built by Bersini] [2] et al. for studying breast cancer metastasis


anti breast cancer drug screening


breast cancer treatment usually includes surgical resection, radiotherapy, chemotherapy and hormone therapy. Due to the lack of effective and accurate evaluation of toxicity and efficacy in preclinical studies, only about 27% of drugs entering the clinical trial stage have been approved for use on the market. The models used in preclinical studies, especially animal models, cannot accurately predict the true reactions of drugs in the human body. Building a breast cancer organ chip platform to simulate the real metabolic process and predict the actual activity of drugs can screen valuable candidate drugs for clinical research


Anti breast cancer drug delivery


The bottleneck of drug metabolism process is whether it can target delivery to tumor to exert its efficacy. Theoretically, the killing degree of anti breast cancer drugs to all cancer cells in the tumor determines the effectiveness of treatment. But in reality, the distribution of drugs depends on the structure and function of the breast tumor vascular system, as well as the transport characteristics of the drugs themselves. Anti cancer therapy based on improved delivery methods requires drugs to pass through complex vascular systems and ultimately reach the tumor area after passing through the endothelial barrier. In order to accurately evaluate the efficacy, toxicity, and in vitro delivery characteristics of anti breast cancer drugs,


Many oral anticancer drugs need to be metabolized by the liver before their therapeutic effects can be exerted. However, because traditional breast cancer models lack organ organ interaction, it is difficult to directly determine the amount of drug metabolites produced and the cytotoxicity to other organs. Hou Yu [3] We have constructed a high-throughput co culture microarray chip for liver and breast tumor cells, which consists of a tumor array chip and a liver tissue array chip. The pores of the liver chip are seeded with liver cells and endothelial cells, while the tumor chip is designed with a cross shaped protrusion to anchor the tumor cells and prevent their detachment. The design also allows breast cancer cells to directly contact the cells of the liver chip. The anticancer biological activities of the anticancer drugs epirubicin and doxorubicin in breast cancer cells have been compared and evaluated, and the toxicity of these compounds in the liver can also be evaluated simultaneously. This model provides a new tool for studying the metabolic process and drug efficacy basis of breast cancer, and is expected to be applied to drug screening based on the co culture model of breast cancer and liver tissue

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Figure 4 The liver breast cancer co culture array chip constructed by Hou Yu [3]


To sum up, breast cancerCompared with traditional in vitro systems, organ chipmodels have multiple advantages, including reproducing the heterogeneity of breast cancer, mimicking the interaction between tumor stroma and remodeling the process of metastasis, and can be applied to research related to drug efficacy, delivery and metabolism. These models are low in manufacturing cost, fast in development, small in size, suitable for high-resolution imaging, and can have high throughput The field of bionics in vitro has not yet reached the level of complexity, but the disease process in vivo is often a complex process with multiple time and space, so the combination of multiple organ chip models will provide more accurate prediction results


Industry standards based on organ chips are gradually being established, and Da Xiang Technology has also actively submitted its self-developed