Fluid_Mechanics_in_Circulating_Tumour_cell.pptx

This is a presentation based on a reasearch paper

1. Fluid Mechanics in Circulating Tumour cell Course:Biofluid Mechanics and Heat Transfer Presented by……… Jannatun Noor Promi Jannatul Raisa Istiak Ahmed Saju ID: 23167008 ID: 23167011 ID: 23167013

2. Content Introduction Workflow Process of Tumour cells Tumor Vasculature & Fluid Mechanics (Primary Tumor) Angiogenesis and fluid mechanics Tumour Vascularity​ Flows in the tiny blood vessels of tumours Microenvironmental characteristics of malignant tumors Flow mediated Tumor Metastases

3. Content Lymphatic and intravascular spread of tumour cells Spreading of components that originate from the tumour CTCs' intravascular journey Therapy Observation Conclusion

4. Introduction Cancer metastasis is a key reason for reduced life expectancy in patients, as tumor cells spread through the blood and lymph systems. Fluid dynamics—such as flow, shear stress, and pressure—affect how cancer cells behave and spread. By understanding these forces, we can create new strategies to target metastasis and improve treatment outcomes. This presentation focuses on how fluid dynamics influence cancer metastasis and how this knowledge could lead to better therapies.

5. Graphical Abstract of Fluid mechanics in Tumour cells

6. Workflow process of Tumour cell 1. Cancer occurs when genetic mutations cause cells to grow uncontrollably and spread, disrupting normal cell functions. These changes affect genes that regulate growth and communication, leading to abnormal cell division and behavior. 2 . Cancer cells called circulating tumor cells (CTCs) break away from the main tumor and travel through the blood, spreading the disease. These cells survive in the blood for a short time, around 1 to 2 hours. Blood, lymph, and other body fluids have different properties based on their structure and makeup. 3. Cancer cells (CTCs) face different forces as they travel through body fluids like blood and lymph. Blood moves quickly due to the heart's pumping, creating stronger forces, while lymph flows slowly and smoothly. Abnormal blood and lymph vessels can help tumors grow and spread. The flow and structure of these fluids play a key role in how cancer cells survive and spread to new areas. CTCs and other material produced by circulating tumours are exposed to shear rates ranging from 10 s to 1 in the lymph19 to 1,000 s–1 in the major arteries .

7. Workflow process of Tumour cell 4. Tissues that are perfused can carry oxygen and nutrients to tumours. At this stage, tumours seldom reach 1 mm3 in size. Based on oxygen diffusion limitations in nearby arteries, the diameter of a vascular tumours is between 100 and 200 m. Without oxygen and nutrients, tumour cells generate a necrotic core. 5. Hypoxic tumours emit proangiogenic chemicals. These chemicals can induce the formation of new blood vessels around an existing tumour . 6. Cancer cells avoid natural death and use blood and lymph flows to spread. They mutate to bypass growth controls, leading to uncontrolled growth and resistance to repair. These cells can get trapped in capillaries, spread, and form new tumors. Tumors produce fluid that aids cancer spread but blocks treatment delivery .

8. Tumor Vasculature & Fluid Mechanics (Primary Tumor) Abnormal Blood Vessels: 1.Irregular, leaky, and poorly organized 2.Lead to uneven blood flow and oxygen supply High Fluid Pressure: 1.Due to leaky vessels and poor lymph drainage 2.Blocks drug delivery to the tumor core Low Oxygen (Hypoxia): 1.Triggers more blood vessel growth (angiogenesis) 2.Makes tumors more aggressive Impact on Treatment: 1.Difficult for drugs to reach the tumor 2.Strategies like normalizing blood vessels or using nanoparticles can help

9. Angiogenesis and fluid mechanics Angiogenesis: Angiogenesis is the process by which new blood vessels form from existing ones. It is essential for growth, wound healing, and supplying oxygen and nutrients to tissues. In diseases like cancer, abnormal angiogenesis can help tumors grow by providing blood supply. Fluid Mechanics : Fluid mechanics is the study of how fluids (liquids and gases) move and interact with forces. It explains phenomena like the flow of blood in vessels, water through pipes, and air around planes. Key concepts include pressure, flow rate, and resistance. Connection: In angiogenesis, fluid mechanics plays a crucial role as blood flow influences where and how new vessels form. Proper flow ensures efficient oxygen delivery and healthy tissue development.

10. Tumour Vascularity Key Aspects of Tumor Vascularity ​ 1 .Angiogenesis – Tumors release factors like vascular endothelial growth factor (VEGF) to promote new blood vessel formation.​ 2 .Hypoxia & Neovascularization – Low oxygen levels in tumors trigger new vessel growth.​ 3 .Tumor Blood Vessel Characteristics – Tumor vessels are often irregular, leaky, and poorly organized compared to normal vessels.​ 4. Imaging & Assessment – Doppler ultrasound, CT angiography, MRI, and PET scans help assess vascularity.​ 5 .Clinical Significance – Highly vascular tumors may grow and spread more aggressively, but also respond better to anti-angiogenic therapies (e.g., bevacizumab).

11. Flows in the tiny blood vessels of tumours ​ Tiny blood vessels in tumors, known as microvasculature, often have abnormal and chaotic blood flow patterns. This is due to the disorganized structure of these vessels, leading to inconsistent oxygen and nutrient delivery. Key characteristics include: Irregular Flow Patterns : Blood flow is often sluggish or turbulent. Hypoxia Zones : Poor blood flow can result in oxygen-deprived tumor regions, contributing to aggressive tumor growth. Angiogenesis : Tumors stimulate the growth of new, abnormal vessels to support their expansion.

12. Microenvironmental characteristics of malignant tumors The tumor microenvironment, made up of surrounding tissue cells and the extracellular matrix (ECM), plays a key role in cancer growth and spread. Fibroblasts, the most common cells in this environment, release substances that stiffen the ECM and increase fluid pressure. This creates mechanical stress, promoting tumor growth, invasion, and the formation of new blood vessels. The stress also causes changes in cell adhesion and gene expression, aiding metastasis. Fibroblasts produce collagen, further stiffening the ECM and helping cancer cells spread.

13. Microenvironmental characteristics of malignant tumors High ECM collagen and stiff tissues are linked to breast cancer development. Changes in matrix stiffness caused by ECM remodeling encourage cancer cell growth and migration. Durotaxis , the movement of cells toward stiffer regions, influences cancer spread into surrounding tissues. Leaky blood vessels around tumors increase interstitial pressure, promoting cell growth and new blood vessels. Tumors expel fluid via the lymphatic system, which alters fibroblasts and stiffens the ECM. Fluid flow changes cytokine gradients, directing cells into lymphatic capillaries. These mechanical changes in the tumor microenvironment affect cancer progression and treatment outcomes.

14. Tumor growth Tumor growth causes a radial solid stress (black arrows), a stiffer  extracellular matrix  (ECM; grey fibers), higher interstitial pressure from  venule  (blue arrows), and a higher rate of interstitial flow (purple, red, & yellow arrows).

15. Flow mediated Tumor Metastases Cancer spreads through the blood and lymph, helping tumors grow elsewhere. This process, called metastasis, causes most cancer deaths. Primary tumors are easier to treat, but metastatic cancer is harder to control. Metastasis steps: Intravasation : Cancer enters blood or lymph. Circulation: Cells travel. Extravasation: Cells exit vessels. Colonization: New tumors form. Only a few cancer cells successfully spread. Understanding metastasis can improve treatments.

16. Flow mediated Tumor Metastases   The spread of metastatic cells is regulated by a network of fluid pathways. Biological and mechanical signals govern the non-random process of  metastasis . Common metastatic patterns for colon, breast, and  pancreatic cancers  are depicted via  anatomical structure  and the accompanying vascular pathways, illustrating how  circulating tumour cells  (CTCs) exploit blood and the  lymphatic circulation  to reach distant organs.

17. Lymphatic and intravascular spread of tumour cells Cancer cells can spread even in the early stages of breast and colorectal cancer. They travel through blood vessels or lymphatic pathways, shedding as single cells or clusters called circulating tumor cells (CTCs). Platelets protect CTCs and promote their spread by slowing blood flow and increasing shear stress. Lymph node metastasis usually occurs before systemic spread and is an important predictor of survival. Tumor cells navigate through lymph nodes and blood vessels, often settling in the lungs or liver due to their small capillaries. Shear forces, blood flow, and cell interactions affect their arrest . Mechanical properties of cancer cells influence metastasis, and targeted drugs can alter their behavior.

18. Spreading of components that originate from the tumour Cancer metastasis involves the spread of tumor cells to distant organs through blood and lymphatic systems. Cells often get trapped in capillaries, where they leak out and begin growing in new locations. Tumor-secreted factors such as chemokines, cytokines, and extracellular vesicles (EVs) influence cancer progression by altering the tumor environment and attracting immune cells. EVs travel quickly through blood and lymph, interacting with the endothelium and being removed by immune cells. They can also prime organs for metastasis by making blood vessels more permeable. Understanding the role of EVs and tumor-secreted chemicals may improve early detection and treatment strategies for cancer.

19. CTCs' intravascular journey Here we will see journey of circulating tumor cells (CTCs) as they navigate the bloodstream and lymphatic system, ultimately aiming to colonize distant organs and establish secondary tumors .

20. Shear Stress: A Double-Edged Sword: Shear stress is a complex factor, with its impact depending not only on the magnitude but also the duration and type of flow encountered . The Power of Partnerships: CTCs clusters and interact with blood components like platelets and neutrophils. These interactions can protect CTCs from immune attacks and shear stress, while platelets may enhance their survival and adhesion.

21. Immune Evasion: A Survival Tactic:  CTCs evade the immune system using multiple strategies to enhance survival and metastasis. They form clusters, interact with platelets and blood components for protection, and can even hijack host cells to shield themselves from immune attacks. EMT and MET: Shape-Shifting for Survival: Epithelial-to-mesenchymal transition (EMT) enables circulating tumor cells (CTCs) to detach from the primary tumor and enter the bloodstream, while mesenchymal-to-epithelial transition (MET) allows them to colonize distant sites. Shear stress can influence EMT, highlighting the role of physical forces in cancer metastasis and cellular transformations.

22.   Intravascular arrest and extravasation While adhesion is essential for arrest, excessive shear can be harmful. Extravasation remains less understood, but the paper highlights the role of cellular mechanisms, shear stress, and immune responses.

23. Intravascular Arrest : CTCs can get stuck in small blood vessels either by blocking them or sticking to the walls. Shear stress helps them stick but can also detach or damage them. The strength of adhesion molecules like CD44 and integrin 1 is key to how tightly they stick. Shear Stress and Extravasation:  Shear stress can activate platelets and endothelial cells, potentially influencing extravasation. The endothelial cells can respond to and clear blockages, which might remove CTCs. Shear stress in lung metastasis can lead to the shedding of CTC fragments, affecting the immune response. Cell Death and Emboli:  CTCs can undergo apoptosis or necroptosis during extravasation. They can also form emboli within blood vessels.

24. Therapy Modulating the tumor microenvironment, using antiangiogenic therapies, exploiting the EPR effect, and developing targeted nanoparticles are all discussed as potential strategies to improve cancer treatment.

25. Challenges in Traditional Therapy Current cancer treatments target the whole body, but drug delivery to tumors is inefficient due to barriers like irregular blood vessels, abnormal tumor structure, and impaired lymphatic drainage. These obstacles limit drug transport and effectiveness. Microenvironment as a Target Modifying the tumor microenvironment can enhance drug delivery by normalizing blood vessels, breaking down the extracellular matrix, increasing blood flow, and restoring lymphatic function. The timing of these interventions is crucial for effectiveness. Antiangiogenic Therapy This approach targets endothelial cells in new blood vessels to inhibit tumor growth. It has side effects like high blood pressure and potential tumor aggressiveness. Combining antiangiogenic drugs with chemotherapy has shown some success.

26. Enhanced Permeability and Retention (EPR) Effect EPR allows macromolecules to accumulate in tumor tissues due to leaky blood vessels and poor lymphatic drainage. Though useful in nanomedicine, it mainly benefits larger tumors and is not effective for all types.. Flow-Mediated Delivery of Nanoparticles Nanoparticles leverage the EPR effect for targeted drug delivery. Their effectiveness depends on size, shape, deformability, and surface properties.

27. Microfluidics and Cancer Microfluidic devices are powerful tools in cancer research. They offer a means to isolate and characterize CTCs, providing valuable insights into cancer metastasis.

28. Importance of CTCs: CTCs are important for understanding cancer spread and improving genetic analysis of tumors (liquid biopsies). Isolating and characterizing CTCs can provide valuable information about metastasis. Microfluidic Devices for CTC Isolation :  Microfluidic devices offer a promising approach for CTC isolation due to their ability to handle small sample volumes and control flow conditions. Biomarker-Based Selection Many microfluidic devices use biomarkers like EpCAM to identify and capture CTCs. However, EpCAM expression can vary, particularly during epithelial-mesenchymal transition (EMT), limiting this method’s effectiveness.

29. Filterless Microfluidic Devices Certain devices use inertial focusing to separate CTCs based on size and other physical characteristics, eliminating the need for filters and reducing clogging risks. Microfluidics for Studying Cell Behavior Microfluidic devices also help analyze cancer cell behavior, including movement and responses to stimuli, by mimicking aspects of the tumor microenvironment in a controlled setting. Flow and Cell Adhesion Microfluidics allows researchers to study how fluid flow affects CTC adhesion to vessel walls. Flow influences cell rolling (mediated by glycoproteins and selectins) and strengthens adhesion, with mechanical forces playing a key role in these processes.

30. Observation This paper explains that the chaotic fluid in tumors makes drug delivery harder, but understanding fluid dynamics could improve treatments. It also suggests that fluid forces could affect cancer spread and immune responses, offering ways to enhance immunotherapies. By combining fluid dynamics with liquid biopsy methods, we could improve cancer diagnosis and treatment. The authors call for a more complete approach to cancer research, combining fluid mechanics with genetics and biochemistry to improve patient outcomes.

31. Conclusion This paper highlights the important but underexplored role of fluid dynamics in cancer spread. While much focus has been on genetic and biochemical factors, blood and lymph flow also play a crucial role. The movement of fluids around tumors could help spread cancer cells, and studying how these fluids affect circulating tumor cells (CTCs) may lead to new ways to predict or treat metastasis. Understanding how fluid forces influence CTCs could open doors to better diagnostics and therapies.

32. References Fluid mechanics in circulating tumour cells : https://doi.org/10.1016/j.medidd.2023.100158 Genetic alteration and gene expression modulation during cancer progression : https://doi.org/10.1186/1476-4598-3-9 Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors : https://doi.org/10.1006/mvre.1996.2005

33. Thank You Any Questions?