Dr. Djeda Belharazem, Senior Scientist Life Sciences djeda.belharazem@biomex.de

Dr. Manish Kumar, VP Sales and Projects manish.kumar@biomex.de

Introduction
Cancer research has traditionally focused on genetic mutations as the primary drivers of tumor development and progression. However, recent advances reveal that cancer is far more complex than a mere collection of genetic alterations. It is a multifaceted and evolving disease, thriving within the intricate ecosystem of its surrounding environment—known as the tumor microenvironment (TME). To combat cancer effectively, researchers must shift their focus beyond mutated cells and towards understanding the dynamic interactions between cancer cells and their environment. This comprehensive approach offers new opportunities for developing innovative therapies aimed at halting tumor progression and metastasis.

The Tumor Microenvironment (TME): A New Frontier in Cancer Research
The tumor microenvironment (TME) presents both challenges and opportunities in the fight against cancer. Composed of a heterogeneous mix of cancer cells, immune cells, fibroblasts, and extracellular matrix (ECM) components, the TME is a dynamic system that plays a crucial role in regulating tumor growth, metastasis, and resistance to therapy (Hanahan & Weinberg, 2011). Traditional cancer therapies, which primarily target cancer cells, often fail due to resistance mechanisms that arise within the TME. This underscores the importance of developing ex vivo preclinical models that mimic the TME to better predict therapy outcomes and develop more effective treatments (Whiteside, 2008). Key players within the TME include tumor-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), which the tumor recruits to support its growth and survival. CAFs contribute to tumor progression by secreting growth factors, remodeling the ECM, and creating a pro-tumorigenic environment (Kalluri, 2016). TAMs, depending on their polarization state, can either promote or inhibit tumor growth (Noy & Pollard, 2014). Understanding the mechanisms that drive these interactions and their role in cancer progression is essential for developing therapies that disrupt the supportive role of the TME.

The Urgent Need for Human-Derived ECM
One of the key challenges in cancer research is the lack of reliable and biologically relevant models to study the TME. Traditional synthetic ECMs are static and fail to capture the complexity of the in vivo human tumor environment (Cox & Erler, 2011). To fully understand cancer‘s mechanisms of resistance and expansion, researchers need an animal-free, human-derived ECM that reflects the dynamic interactions between tumor cells, CAFs, TAMs, and other TME components. A 100% human-derived ECM offers an innovative solution by providing a more interactive and accurate environment for human cell research. This allows for a deeper understanding of how the TME influences cancer progression, metastasis, and therapy resistance.

Epithelial-Mesenchymal Transition (EMT) and Metastasis
Metastasis is the leading cause of cancer-related deaths, responsible for over 90% of such fatalities (Chaffer & Weinberg, 2011). The process of metastasis involves a series of complex steps, beginning with epithelial-mesenchymal transition (EMT). During EMT, tumor cells lose their epithelial characteristics and gain mesenchymal traits, enabling them to migrate from the primary tumor site (Nieto et al., 2016). TME plays a pivotal role in this process by providing the signals that drive EMT and support tumor cell invasion into surrounding tissues. Once tumor cells escape the primary site, they enter the bloodstream and eventually colonize distant organs, forming secondary tumors.
Understanding the role of the TME in metastasis is crucial for developing therapies that can prevent the spread of cancer. Human-derived ECM models, such as homoGel®, provide an ideal platform for studying the signals and interactions that drive EMT and metastasis, offering new insights into how cancer cells establish new tumors in distant organs.

ECM and Vascularization
The formation of blood vessels, or vascularization, is essential for both tumor growth and tissue regeneration. In cancer, tumor cells rely on new blood vessels to supply nutrients and oxygen, enabling them to grow and metastasize (Hanahan & Folkman, 1996). In regenerative medicine, vascularization is equally important for ensuring the survival and integration of newly engineered tissues. Human-derived ECMs, like homoGel®, provide a critical platform for studying the role of ECM in vascularization and developing therapies that can either promote or inhibit blood vessel formation, depending on the desired outcome.

Extracellular Matrix (ECM) and Stem Cells in Regenerative Medicine
The ECM is fundamental to regenerative medicine, serving as a dynamic scaffold that regulates cell behavior, tissue growth, and organ regeneration. In tissue engineering and regenerative therapies, the ECM‘s structural and biochemical cues guide the differentiation, proliferation, and function of cells, especially stem cells. Advances in human-derived ECM, such as homoGel®, offer new opportunities for creating biologically relevant models that are crucial for advancing therapeutic development.

The Role of ECM in Stem Cell Therapy
Stem cells, particularly mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), hold vast potential in regenerative medicine due to their ability to differentiate into various cell types. However, the effectiveness of stem cell therapies is highly dependent on the surrounding ECM, which provides critical biochemical signals and mechanical support that maintain the stemness of these cells (Chen et al., 2021). Traditional synthetic ECMs, such as polyethylene glycol (PEG)-based hydrogels, lack the biological complexity needed to replicate the human in vivo environment. These synthetic materials often fail to support cell differentiation and tissue regeneration. In contrast, human-derived ECMs, like homoGel®, contain native biochemical signals that closely mimic human tissue, ensuring that MSCs and iPSCs maintain their ability to self-renew and differentiate into functional tissue (Yin et al., 2021).
Recent studies suggest that human derived ECMs can influence stem cell fate by promoting specific lineage commitments, such as osteogenesis or chondrogenesis, in tissue-specific environments. This indicates that human-derived ECMs, like homoGel®, could serve as a more effective platform for creating tissue-specific regenerative therapies (Lau et al., 2021).

ECM in Tissue Engineering and Organ Reconstruction
Tissue engineering requires an ECM that provides structural integrity and promotes the formation of functional tissues. Human-derived ECMs, like homoGel®, offer superior platforms for engineering tissues by providing essential growth factors, structural proteins, and mechanical properties needed to support the formation of complex tissues such as skin, cartilage, and bone (Gao et al., 2021).
In organ reconstruction, vascularization is a critical challenge. Without a robust blood supply, engineered tissues cannot survive or integrate with host tissues. Human derived ECMs have been shown to promote angiogenesis by providing the necessary biochemical signals for forming new blood vessels (Jang et al., 2022). homoGel®’s human-specific composition allows it to effectively support the growth of new vasculature, essential for developing functional tissues and organs.
Recent research has demonstrated that using human-derived ECM scaffolds improves outcomes in reconstructing organs like the liver and kidney, where vascularization is vital for long-term functionality. By promoting a native-like environment, homoGel® has the potential to significantly enhance the success rate of organ engineering and transplantation (Zhao et al., 2021).

Summary
The development of 100% human-derived ECMs marks a significant advancement in cancer research and regenerative medicine. homoGel® offers researchers a powerful tool to better understand the complexities of the TME and its role in cancer progression. Additionally, homoGel®‘s applications in tissue engineering and regenerative medicine hold great promise for advancing therapeutic development and improving patient outcomes. The future of healthcare lies in replicating the human body‘s natural systems, and homoGel® is at the forefront of this revolution.

References

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