The Role of Mesenchymal Stromal Cells in Breast Cancer Doxorubicin Resistance through Hyaluronan Production
Breast cancer is one of the most common types of cancer affecting women worldwide. Despite significant advancements in treatment options, drug resistance remains a major challenge in the management of breast cancer. One particular drug commonly used in breast cancer treatment is doxorubicin, a chemotherapy agent that works by inhibiting the growth of cancer cells. However, many breast cancer patients develop resistance to doxorubicin, leading to treatment failure and disease progression.
Recent studies have shed light on the role of mesenchymal stromal cells (MSCs) in breast cancer doxorubicin resistance. MSCs are a type of adult stem cell found in various tissues, including bone marrow and adipose tissue. They have the ability to differentiate into different cell types and play a crucial role in tissue repair and regeneration. In the context of breast cancer, MSCs have been shown to contribute to tumor growth, metastasis, and drug resistance.
One mechanism through which MSCs promote doxorubicin resistance in breast cancer is by producing hyaluronan, a large polysaccharide molecule found in the extracellular matrix. Hyaluronan is involved in various physiological processes, including cell migration, proliferation, and inflammation. In breast cancer, high levels of hyaluronan have been associated with poor prognosis and increased resistance to chemotherapy.
Studies have demonstrated that MSCs can secrete hyaluronan in response to signals from breast cancer cells. This hyaluronan production creates a protective microenvironment around the tumor, shielding it from the effects of doxorubicin. The increased hyaluronan levels contribute to the formation of a dense extracellular matrix, which hinders drug penetration into the tumor and reduces its efficacy.
Furthermore, hyaluronan has been shown to activate signaling pathways that promote cancer cell survival and drug resistance. It can interact with specific cell surface receptors, such as CD44, and activate downstream signaling molecules, including Akt and ERK, which are involved in cell survival and proliferation. These signaling pathways can enhance the expression of drug efflux pumps, such as P-glycoprotein, which actively pump doxorubicin out of the cancer cells, reducing its intracellular concentration and effectiveness.
In addition to hyaluronan production, MSCs can also directly interact with breast cancer cells and promote their survival and resistance to doxorubicin. MSCs can transfer mitochondria to cancer cells through tunneling nanotubes, a form of intercellular communication. This mitochondrial transfer enhances the energy production capacity of cancer cells, making them more resistant to the cytotoxic effects of doxorubicin.
Understanding the role of MSCs in breast cancer doxorubicin resistance is crucial for developing strategies to overcome this resistance and improve treatment outcomes. Targeting the interaction between MSCs and breast cancer cells, as well as inhibiting hyaluronan production, could potentially enhance the efficacy of doxorubicin and other chemotherapy agents.
Several approaches are being explored to target MSCs in breast cancer therapy. These include using small molecule inhibitors to block hyaluronan synthesis or disrupt its interaction with CD44 receptors. Additionally, strategies to inhibit mitochondrial transfer from MSCs to cancer cells are being investigated.
In conclusion, mesenchymal stromal cells play a significant role in breast cancer doxorubicin resistance through the production of hyaluronan. This polysaccharide molecule creates a protective microenvironment around the tumor, hinders drug penetration, and activates signaling pathways that promote cancer cell survival and drug resistance. Understanding these mechanisms opens up new avenues for developing targeted therapies to overcome doxorubicin resistance in breast cancer patients and improve treatment outcomes.
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- Source: Plato Data Intelligence.
- Source Link: https://platohealth.ai/mesenchymal-stromal-cells-confer-breast-cancer-doxorubicin-resistance-by-producing-hyaluronan-oncogene/