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EFFECTS OF MICROGRAVITY ON THYROID CANCER

1. ABSTRACT

Microgravity, often encountered in space environments and described as low gravity, exerts profound effects on human physiology. The impact of microgravity on cancer cells, especially thyroid cancer cells, is a relatively new field of research (1,2). Thyroid cancer, whose global incidence is on the rise (3,4), comprises several distinct subtypes at the cellular and molecular levels (5–8). In recent years, platforms such as CELLBOX-2 on space stations (9) and short-duration suborbital rocket missions like TEXUS-53 (10) have provided valuable insights into how thyroid cancer cells might behave under microgravity.

This thesis investigates, in light of the existing literature, the potential effects of microgravity on fundamental biological functions—such as proliferation, gene expression, migration, and apoptosis—of thyroid cancer cells. Early chapters summarize the molecular pathophysiology of thyroid cancer and current treatment approaches; subsequent chapters define microgravity, present simulation methods (e.g., rotary wall vessel, random positioning machine), and examine spaceflight missions (CELLBOX-2, TEXUS-53). After reviewing microgravity research on various human cell types (immune, endothelial, osteoblast, etc.), the focus turns to in-depth analyses of thyroid cancer–specific studies. Finally, the findings are synthesized, and suggestions for future research are provided.

The available data suggest that microgravity may exert complex, and sometimes paradoxical, effects on thyroid cancer cells—both suppressive and stimulatory (11,12). Such phenomena likely stem from diverse biological mechanisms including mechanotransduction, integrin signaling, and epigenetic modifications (e.g., miRNAs) (19,21,28). As space medicine and Earth-based oncology continue to intersect, the importance of these studies grows (13).

Keywords: Microgravity, Thyroid Cancer, CELLBOX-2, TEXUS-53, Space Biology, Gene Expression, Mechanotransduction

2. INTRODUCTION

2.1. Background and Rationale

Space exploration, particularly since the mid-20th century, has driven investigations into how the human body adapts to environments beyond Earth. Early efforts prioritized major physiological changes such as skeletal muscle atrophy and immune suppression (1,2). Recently, however, attention has turned to how microgravity might influence cancer cells, especially those of endocrine origin (11).

Thyroid cancer is the most common endocrine malignancy (3,4), comprising papillary, follicular, medullary, and anaplastic subtypes (5–8). At the molecular level, these subtypes are characterized by various mutations and alterations along the MAPK (RAS-RAF-MEK-ERK) and PI3K/AKT pathways (7,18). Surgical resection, radioactive iodine (RAI) ablation, and new-generation tyrosine kinase inhibitors (TKIs) are main treatment strategies on Earth (5,6,20). Nevertheless, outcomes for advanced or aggressive variants (e.g., anaplastic thyroid cancer) remain unsatisfactory (6).

Microgravity may fundamentally alter how cells perceive and respond to mechanical forces (mechanotransduction) (21). In this context, platforms like CELLBOX-2 (operating aboard the ISS) and TEXUS-53 (providing a short but genuine microgravity environment) hold potential to shed light on how thyroid cancer cells adapt to minimal mechanical loading (9,10). Preliminary findings in other cancer cell lines suggest that microgravity can reduce proliferation in some cells while enhancing migration or metastatic behavior in others (11,12).

2.2. Research Aims and Questions

This thesis aims to compile and analyze existing literature on how thyroid cancer cells respond under microgravity conditions. The primary research question is:

“What are the effects of microgravity on the key biological features of different thyroid cancer subtypes (proliferation, apoptosis, gene expression, migration), and what implications might these have for space medicine and Earth-based oncology?”

Supporting sub-questions include:

1. Which molecular pathways (MAPK, PI3K/AKT, integrin/FAK, etc.) are most affected by microgravity?

2. How do short-duration (e.g., TEXUS-53) and long-duration (CELLBOX-2, ISS-based) microgravity conditions differ in their impact on thyroid cancer cells?

3. What similarities and differences exist between ground-based microgravity simulations (rotary wall vessel, random positioning machine) and real spaceflight data?

4. How might these research outcomes inform new strategies in thyroid cancer treatment or astronaut endocrine health?

2.3. Thesis Organization

This thesis comprises eight main chapters:

· Chapter 1 (Abstract): Provides a concise overview of the thesis.

· Chapter 2 (Introduction): Explains the study’s background, aims, and importance.

· Chapter 3 (Overview of Thyroid Cancer): Addresses thyroid cancer epidemiology, classification, molecular pathophysiology, and current treatments.

· Chapter 4 (Microgravity: Definition, Simulation, and Biological Implications): Defines microgravity, discusses simulation methods, and highlights missions like CELLBOX-2 and TEXUS-53.

· Chapter 5 (Effects of Microgravity on Human Cells): Reviews how various human cell types—including immune, osteoblast, endothelial, and cancer cells—respond to microgravity.

· Chapter 6 (Effects of Microgravity on Thyroid Cancer): Focuses on specific thyroid cancer studies.

· Chapter 7 (Synthesis and Discussion): Integrates the findings, explores mechanisms, and identifies research gaps.

· Chapter 8 (Conclusions): Summarizes core results and makes recommendations for future studies.

Overall, the thesis offers a thorough perspective on how thyroid cancer might change under microgravity from both a space biology and an oncology standpoint.

3. OVERVIEW OF THYROID CANCER

3.1. Anatomy and Physiology of the Thyroid Gland

Situated at the front of the neck, just below the larynx, the thyroid gland has a butterfly shape (14). Follicular cells produce and store T3 and T4 hormones, while parafollicular cells secrete calcitonin for calcium homeostasis (15). Thyroid hormones regulate metabolism, growth, and development, affecting numerous bodily processes.

Figure I: The thyroid gland is located anteriorly in the neck, just below the larynx, and is composed of two lobes connected by an isthmus. Figure I illustrates the thyroid cartilage, the gland itself, and a representative tumor site.

3.2. Epidemiology of Thyroid Cancer

The incidence of thyroid cancer has risen significantly in the past two decades (3,4). In developed countries, the detection of smaller papillary microcarcinomas via ultrasound partly explains this trend (16). Females are disproportionately affected, and diagnosis often occurs between the ages of 25 and 65 (4).

3.3. Classification and Histopathology

According to the World Health Organization (WHO), thyroid cancers are divided into four primary subtypes: papillary, follicular, medullary, and anaplastic (17). Papillary (accounting for ~80–85%) is most common (5,18); follicular involves RAS mutations and PAX8-PPARγ fusions (7). Medullary arises from parafollicular C cells, often harboring RET mutations (8). Anaplastic is highly aggressive, with poor therapeutic outcomes (6).

3.4. Molecular Pathophysiology

Crucial pathways in thyroid carcinogenesis include MAPK (RAS-RAF-MEK-ERK) and PI3K/AKT (18). For instance, in papillary carcinoma with a BRAF^V600E mutation, cell proliferation may increase while apoptosis is suppressed. Epigenetic regulators—such as DNA methylation and miRNAs—also play a key role (19).

Worldwide, targeted therapies (e.g., tyrosine kinase inhibitors) have emerged for these molecular abnormalities (20). However, for highly aggressive or metastatic thyroid cancers, outcomes remain suboptimal (6).

Figure II: Figure II illustrates these two major signaling pathways and highlights how upstream receptors, intracellular kinases, and nuclear transcription events are integrated in thyroid tumorigenesis.

3.5. Current Therapeutic Approaches and Challenges

Differentiated thyroid cancers (papillary, follicular) are typically manageable via surgery (total or partial thyroidectomy) and radioactive iodine ablation (5). For RAI-refractory cases, targeted therapies (lenvatinib, sorafenib) are used, though they can have serious side effects (20). In medullary cancer, calcitonin levels guide follow-up; in anaplastic, even combining aggressive surgery, chemotherapy, and radiotherapy often fails to yield satisfactory results (6).

Thus, environmental factors like microgravity could offer fresh perspectives on cancer biology, potentially unveiling novel therapeutic angles (11,12).

4. MICROGRAVITY: DEFINITION, SIMULATION, AND BIOLOGICAL IMPLICATIONS

4.1. Defining Microgravity and Spaceflight Conditions

In low Earth orbit, spacecraft experience continuous “free fall” around Earth (9). This results in what feels like weightlessness or “microgravity.” True gravity is not nullified, but the balance of forces dramatically reduces perceived gravitational pull (2).

· Orbital Missions (ISS): Experiments can last months.

· Suborbital Missions (TEXUS-53): Provide around 6–8 minutes of microgravity (10).

· CELLBOX-2: An advanced cell culture platform aboard the ISS, offering real-time monitoring and sampling (9).

Table I Comparison of various microgravity platforms by duration and key characteristics.

4.2. Ground-Based Analogs and Simulation Techniques

Because spaceflight is not always accessible or economical, ground-based approaches include:

· Rotary Wall Vessel (RWV): Maintains cells in continuous suspension with low shear forces (1,11).

· Random Positioning Machine (RPM): Randomly orients samples in three axes, distributing gravity vectors (2).

· 2D Clinostat: Rotates samples around a single axis.

While these methods can reproduce some aspects of microgravity’s impact, they do not fully replicate space radiation, fluid shifts, or psychological factors (13).

4.3. Mechanotransduction and Cellular Response

Cells detect mechanical forces via integrins and the cytoskeleton (actin filaments, microtubules, intermediate filaments) and convert them into biochemical signals (21). Under microgravity, these forces lessen, reorganizing the cytoskeleton and altering related pathways (FAK-Src, MAPK, PI3K/AKT) (1,11).

In cancer cells, reduced mechanical cues can decrease proliferation in some scenarios, yet increase migration or invasion in others (12). This diversity is influenced by factors such as the tumor’s genetic background and specific culture conditions.

4.4. Historical Context: Studying Cells in Microgravity (Including CELLBOX-2 and TEXUS-53)

Cellular research in microgravity dates to the Skylab era, followed by the Space Shuttle program (1). In the ISS era, immune cells, endothelial cells, osteoblasts, and certain cancer cell lines have undergone prolonged observation (2,11).

· CELLBOX-2: A modular, automated platform for cell cultures on the ISS, capable of controlling temperature, imaging, and fluid changes (9).

· TEXUS-53: Employs sounding rockets for about 6–8 minutes of microgravity (10), ideal for capturing rapid cellular responses.

Although limited data exist for thyroid cancer specifically, these missions hold promise for identifying the mechanobiological sensitivities of tumors.

5. EFFECTS OF MICROGRAVITY ON HUMAN CELLS

Before examining thyroid cancer research directly, it is crucial to understand microgravity’s general effects on human cells. Immune cells, osteoblasts, endothelial cells, and various cancer cell lines serve as relevant points of comparison.

5.1. Immune Cells

Microgravity frequently induces immunosuppression, with reduced T-lymphocyte proliferation and NK cell activity (1,2,22). Disruptions in protein kinase C signaling and cytoskeletal reorganization underlie these effects. Diminished immune surveillance may theoretically heighten cancer risk (13).

5.2. Osteoblasts and Osteoclasts

Astronauts often experience bone density losses, attributed to disruptions in osteoblast–osteoclast homeostasis (23). Ground-based analogs demonstrate decreased differentiation markers (ALP, osteocalcin) in osteoblasts and increased proliferation in osteoclast precursors (24). Thus, the skeletal system is notably vulnerable to microgravity.

Table II: Observed cellular changes under microgravity in various cell types (immune, bone-related, endothelial, and cancer cells).

5.3. Endothelial Cells and Vascular Biology

Under microgravity, endothelial cells undergo cytoskeletal changes, varying nitric oxide production, and shifts in growth factor expression (25). These changes bear relevance for tumor vascularization (angiogenesis), as vascular–tumor microenvironment interactions are key to growth and metastasis (26).

5.4. Cancer Cells in General (Breast, Lung, Prostate, etc.)

Studies in some solid tumor cell lines (breast, lung) show reduced proliferation yet increased invasion under microgravity (11,27). This paradox may arise from cytoskeletal collapse and reorganization of integrin–focal adhesion signaling (21). Epigenetic regulators (DNA methylation, miRNA expression) appear significantly affected (19,28).

5.5. Potential Mechanisms Underlying Observed Changes

Key mechanisms proposed to explain responses to microgravity include:

1. Tensegrity Disruption: Reduced tension in the cytoskeleton and cell–matrix attachments can alter nuclear shape and chromatin organization (21).

2. Integrin–FAK Axis: Microgravity impedes integrin clustering and focal adhesion formation, affecting proliferation and motility (11).

3. Epigenetic Remodeling: Shifts in miRNA and DNA methylation profiles (28) may trigger long-term phenotypic changes.

6. EFFECTS OF MICROGRAVITY ON THYROID CANCER

Having discussed the general impact of microgravity on various human cells, this chapter evaluates the still-limited but emerging literature on thyroid cancer and outlines prospective avenues for further investigation.

Figure III: Figure III compares normal versus cancer cell morphology under normal gravity and microgravity conditions, highlighting potential differences in shape, size, and cluster formation.

6.1. In Vitro Models and Findings

6.1.1. Follicular Thyroid Carcinoma (FTC) Cell Lines

In the literature, FTC-133 is frequently studied under microgravity simulations. For instance, rotary wall bioreactor experiments have reported reduced proliferation, cytoskeletal reorganization, and MAPK pathway suppression (11,12). Some studies, however, noted increased cell migration under the same conditions (12). These paradoxes may stem from variables such as culture duration, media composition, and inherent genetic traits.

6.1.2. Papillary Thyroid Carcinoma (PTC) Cell Lines

Fewer data exist on papillary thyroid carcinoma (e.g., BCPAP, TPC-1). Shi and colleagues used a random positioning machine (RPM) to observe significant changes in certain miRNAs in BCPAP cells (28). These miRNAs influence tumor aggressiveness and differentiation.

6.1.3. Other Subtypes

Medullary (MTC) and anaplastic (ATC) thyroid cancer cell lines have rarely been investigated under microgravity. Preliminary reports suggest that anaplastic cells may experience extreme cytoskeletal disruption and cell death, but peer-reviewed details remain scarce (6).

6.2. In Vivo and Ex Vivo Investigations

6.2.1. Rodent Models

While rodent models are commonly used to examine bone loss, muscle atrophy, or immune changes in space missions (2,23), in vivo studies focusing on thyroid cancer remain rare. Beck and colleagues (29) discuss the possibility of observing thyroid tumor formation under spaceflight conditions, although comprehensive data are currently lacking.

6.2.2. Ex Vivo Tissue Cultures

Some researchers culture patient-derived thyroid tumor tissue slices in 3D systems or under conditions mimicking microgravity (30). These setups partially preserve stromal and immune microenvironment components, offering more realistic data than 2D monocultures. Short-duration microgravity platforms like TEXUS-53 (10) could test acute tissue responses.

6.3. Key Molecular Pathways Impacted

From the limited but growing evidence, microgravity in thyroid cancer seems to affect:

· MAPK/ERK: Often suppressed under microgravity (11).

· Integrin–FAK: Reduced focal adhesions alter cell adhesion and signaling (21).

· PI3K/AKT: May be mechano-sensitive in FTC and PTC subtypes (7).

· Epigenetic Regulators (miRNAs, DNA methylation): Notably shifted in BCPAP and FTC-133 cells (28).

6.4. Role of Epigenetics and Other Emerging Factors

Microgravity exposure—short- or long-term—can trigger epigenetic modifications that potentially drive enduring changes in gene expression (19,28). If 3D tumor models include immune cells and stromal fibroblasts, more realistic data could be obtained (30). Furthermore, the combined effect of radiation (particularly in extended space missions) and microgravity remains underexplored (13).

7. SYNTHESIS AND DISCUSSION

7.1. Integrating Findings from Literature

Data indicate that microgravity can produce complex, sometimes contradictory effects on thyroid cancer cells. In certain studies, proliferation decreases while migration or invasion increases (11,12). This highlights the intricate consequences of mechanotransduction in cancer cells (21).

· Short-Duration Microgravity (TEXUS-53): Offers a few minutes of real microgravity, facilitating analysis of acute molecular responses (e.g., calcium signaling, early gene expression) (10).

· Long-Duration Microgravity (CELLBOX-2, ISS): Experiments lasting days or weeks can capture cytoskeletal adaptation, epigenetic changes, or the formation of tumor-like structures (9).

Combining insights from both approaches may help dissect how thyroid cancer cells adapt to microgravity over time.

7.2. Mechanisms of Microgravity-Induced Modulation

Cell–cell adhesions, integrin signaling, and the nuclear scaffold all respond to decreased mechanical forces (21). BRAF^V600E or RAS mutations in specific thyroid cancer subtypes may intensify or diminish these responses (5,7). For instance, if ERK activity is suppressed by microgravity in BRAF mutant cells, proliferation might drop, but loss of focal adhesions could simultaneously boost migratory potential.

7.3. Knowledge Gaps and Research Challenges

1. Subtype Coverage: FTC-133 is best studied, whereas papillary, medullary, and anaplastic lines lack sufficient data (6,8).

2. Model Limitations: 2D cultures do not capture the full tumor microenvironment (30).

3. Simulation vs. Real Flight: Ground-based devices (rotary wall vessel) cannot replicate space radiation or fluid dynamics (2,13).

4. Long-Term Effects: The influence of weeks to months of microgravity on thyroid cancer remains unknown.

5. Combined Radiation–Microgravity: The synergy or antagonism between cosmic radiation and low gravity, critical for deep space missions, is poorly understood (13).

7.4. Implications for On-Earth Oncology and Space Medicine

From a space medicine standpoint, monitoring thyroid function and assessing tumor risk in astronauts is essential (2,13). On Earth, findings from microgravity simulations may clarify the role of mechanical loading in cancer pathophysiology. Interventions targeting the integrin–focal adhesion axis might emerge as novel treatments (11,21). Additionally, epigenetic data could lead to new diagnostic or prognostic markers for aggressive thyroid cancer (19,28).

8. CONCLUSIONS

8.1. Summary of Key Points

1. Diversity of Thyroid Cancer: Papillary, follicular, medullary, and anaplastic subtypes feature distinct genetic mutations and clinical courses (5–8).

2. Microgravity’s Influence: It can significantly reorganize the cytoskeleton, alter integrin signaling, and induce epigenetic changes (1,11,12,21).

3. CELLBOX-2 and TEXUS-53: Long- versus short-duration microgravity experiments highlight future directions for studying thyroid cancer (9,10).

4. Multilayered Mechanisms: MAPK, PI3K/AKT, epigenetic factors, and tumor–microenvironment interactions make responses to microgravity complex (7,19,28).

5. Clinical Significance: Research findings hold promise for protecting astronaut health and developing new therapies on Earth (13,20).

8.2. Recommendations for Future Research

· More Cell Lines: Investigate papillary (BCPAP, TPC-1) and anaplastic (ATC) thyroid cancer lines under actual spaceflight or simulated conditions.

· 3D Culture and Organoid Models: Incorporate stromal and immune cells to realistically mirror the tumor microenvironment (30).

· Extended Observations: Use CELLBOX-2 to conduct multi-week experiments to track epigenetic changes (9).

· Radiation–Microgravity Interaction: Examine how cosmic radiation interacts with microgravity, especially in deep-space missions (13).

· Clinical Applications: Consider how integrin/FAK or MAPK pathways—highly sensitive to mechanical stress—could be pharmacologically targeted (11,21).

In conclusion, the effects of microgravity on thyroid cancer remain an emerging area of inquiry. Yet, current evidence underscores the significant role of mechanical forces in shaping cancer cell biology. Deepening this knowledge may lead to breakthroughs in both space biology and clinical oncology.

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