hallmarks of cancer, recent and emerging characteristics

this powerpoint discusses the recent hallmarks of cancer and also discusses the emerging characteristics of cancer, from discussion of microbiota as an emerging characteristic to cellular senescence as an enabling characteristic

1. Tumor-Promoting Inflammation: An Enabling Characteristic of Cancer

2. Historical Perspective on Tumor-Associated Inflammation Dense infiltration of immune cells observed in tumors (Dvorak, 1986) Initially thought to represent anti-tumor immune response (Page`s et al., 2010)

3. Tumor-Promoting Effects of Inflammation Emerging evidence suggests inflammation can paradoxically promote tumorigenesis ( DeNardo et al., 2010; Grivennikov et al., 2010) Innate immune cells, particularly myeloid-derived suppressor cells (MDSCs), play a key role in this process (Qian and Pollard, 2010)

4. Mechanisms of Inflammation-Mediated Tumor Promotion Secretion of bioactive molecules into the tumor microenvironment: Growth factors (proliferative signaling) Survival factors (limiting cell death) Proangiogenic factors (blood vessel formation) Extracellular matrix-modifying enzymes (invasion & metastasis) EMT-activating signals (epithelial-to-mesenchymal transition) ( DeNardo et al., 2010; Grivennikov et al., 2010; Qian and Pollard, 2010; Karnoub and Weinberg, 2006–2007)

5. Inflammation and Early Stages of Cancer Development Inflammation can foster development of incipient neoplasias

6. Mutagenic Effects of Inflammation Inflammatory cells can release reactive oxygen species (ROS) ( Grivennikov et al., 2010) ROS can cause mutations in nearby cancer cells, accelerating malignant evolution

7. Conclusion: Inflammation as an Enabling Characteristic Inflammation contributes to acquisition of core hallmark capabilities of cancer Considered an enabling characteristic of cancer development

8. Emerging Hallmarks and Enabling Characteristics

9. Douglas Hanahan; Hallmarks of Cancer: New Dimensions.  Cancer Discov  1 January 2022; 12 (1): 31–46.  https://doi.org/10.1158/2159-8290.CD-21-1059

10. Douglas Hanahan; Hallmarks of Cancer: New Dimensions.  Cancer Discov  1 January 2022; 12 (1): 31–46.  https://doi.org/10.1158/2159-8290.CD-21-1059

11. Unlocking Phenotypic plasticity: Reversing Differentiation

12. Terminal Differentiation: A Barrier to Cancer Terminal differentiation: The process by which cells become specialized, typically losing their ability to proliferate. Functions as a natural safeguard against uncontrolled cell growth. Characterized by changes in: Gene expression Cell morphology Function

13. Phenotypic plasticity allows cancer cells to evade terminal differentiation, promoting continued proliferation. Mechanisms include: Dedifferentiation: Reversal to a progenitor-like state increases proliferative potential. Blocked differentiation: Maintains cells in a partially differentiated, proliferative state. Transdifferentiation : Shift towards a different cell lineage, often promoting invasion and metastasis.

14. Dedifferentiation: Reversing Cell Fate Definition: Cancer cells regress to a less differentiated, often more stem-cell-like state, increasing their proliferative potential. “BACKTRACK” Mechanisms: Loss of factors that promote differentiation (e.g., HOXA5, SMAD4). Upregulation of factors that promote a less differentiated, progenitor-like state (e.g., MITF, specific miRNAs). Dedifferentiation observed in: Colon cancer Melanoma Pancreatic carcinomas

15. Blocked Differentiation: Trapped in a Proliferative State Definition: Cancer cells become 'stuck' in a partially differentiated state, maintaining their ability to proliferate. Mechanisms: Disrupted transcription factors (e.g., PML-RAR α fusion in APL, AML1-ETO in AML) Aberrant developmental regulators (e.g., SOX10 in melanoma) Altered metabolite production (e.g., D2HG in IDH1/2-mutated cancers) Clinical Implications: Blocked differentiation fuels leukemia progression and can promote resistance to differentiation-inducing therapies.

16. Definition: Progenitor/stem cells exit the cell cycle, becoming dormant in protective niches. They retain the potential to re-initiate proliferation while being resistant to differentiation cues. Clinical Implications Contributes to cancer dormancy and later relapse. Poses a challenge to therapies that rely on active cell proliferation. Circumvented Differentiation: Dormancy and Resistance

17. Transdifferentiation : switching cell fates Definition: cancer cells adopt phenotypic trains of a different cell lineage or state. This can occur through tissue metaplasia Eg Barrett’s esophagus Mechanisms: Alterations in transcription factors (PTF1a, MIST1, SOX9, SOX2) Epigenetic reprogramming Clinical implications: Promotes tumor heterogeneity Significant driver of therapeutic resistance Can increase the risk of cancer development (ex: Barrett's esophagus and esophageal adenocarcinoma)

18. PANCREATIC CANCER

19. PROSTATE CANCER

20. BASAL CELL CARCINOMA

21. LUNG CANCER

22. Nonmutational epigenetic reprogramming

23. Nonmutational epigenetic reprogramming

24. There's a growing case for nonmutational epigenetic reprogramming, which involves changes in gene expression without direct DNA mutations. This mechanism mirrors epigenetic regulation in development and differentiation. Nonmutational epigenetic mechanisms may also contribute to cancer hallmarks.

25. Microenvironmental Mechanisms of Epigenetic Reprogramming If not solely due to mutations, how is the cancer cell genome reprogrammed? Evidence suggests that the physical properties of the tumor microenvironment can cause broad epigenetic changes, enabling cancer cells to develop hallmark capabilities.

26. Hypoxia A common feature in tumors Reduces the activity of TET demethylases, which normally remove methyl groups from DNA Results in hypermethylation, showing significant change in the epigenome.

27. Hypoxia and Ependymoma Pediatric ependymoma is a type of brain cancer that often lacks typical cancer-driving mutations. Growth in this cancer is driven by a gene regulatory program triggered by hypoxia. The cell-of-origin likely resides in a hypoxic area, making it vulnerable to this type of epigenetic reprogramming.

28. INVASIVE GROWTH AND EMT epithelial-to-mesenchymal transition (EMT) program. = invasiveness ZEB1, a master regulator of EMT, promotes the expression of the histone methyltransferase SETD1B. In a positive feedback loop, SETD1B maintains ZEB1 expression, stabilizing the invasive EMT state. Additional EMT transcription factors include SNAIL1, SLUG, and TWIST. EMT is strongly associated with metastasis and poor prognosis in several malignancies, including lung and pancreatic and colorectal carcinomas

29. The Epithelial-to-Mesenchymal Transition (EMT) EMT is a developmental program where epithelial cells lose their polarity and cell-cell adhesion, acquiring a migratory mesenchymal phenotype. Cancer cells can hijack EMT to gain invasive properties, facilitating metastasis. Key changes in EMT include: Decreased cell-cell adhesion molecules (e.g., E-cadherin) Increased matrix-degrading enzymes Upregulation of mesenchymal markers ( e.g.,vimentin ) EMT is regulated by transcription factors like ZEB1, SNAIL, and TWIST.

30. Paracrine Signaling and Invasiveness

31. Intratumoral heterogeneity Cancer cells within a single tumor can exhibit significant phenotypic diversity, contributing to malignant progression. arises from both genetic instability and non-mutational, epigenetic mechanisms.

32. Epigenetic Heterogeneity

33. Partial EMT and Dynamic States Partial EMT (p-EMT) is an example of epigenetically regulated plasticity in cancer. In p-EMT, cancer cells at the tumor's invasive margins lack classic EMT transcription factors but exhibit other EMT-associated characteristics. p-EMT states are dynamic and reversible, even without genetic changes.

34. Profiling epigenetic Heterogeneity Genome-wide profiling technologies enable the study of epigenetic heterogeneity in cancer. Key techniques include: DNA methylation profiling NSCLC – RASSF1A, CDKN2A, APC Histone modification analysis Chromatin accessibility mapping

35. STROMAL CELLS IN THE TME The tumor microenvironment (TME) includes non-cancerous cells that can be reprogrammed to support tumor growth. Key stromal cell types include: Cancer-associated fibroblasts (CAFs) Innate immune cells Endothelial cells and pericytes Stromal cells are primarily reprogrammed through epigenetic changes induced by the TME, rather than genetic mutations.

36. Epigenetic Reprogramming of Stromal Cells The tumor microenvironment (TME) reprograms stromal cells through soluble signals (cytokines, chemokines, growth factors). These signals induce epigenetic changes that alter gene expression patterns in stromal cells. Reprogrammed stromal cells acquire tumor-promoting behaviors, distinct from mutation-driven changes in cancer cells.

37. Stromal Epigenetic Reprogramming

38. Polymorphic Microbiomes

39. Gut Microbiome and Cancer Risk The gut microbiome plays a fundamental role in colon health. Decades of research have suggested a potential link between the gut microbiome and colon cancer risk. Recent studies, including those involving fecal transplants, have definitively established this connection. Specific bacterial species within the gut can have either protective or tumor-promoting effects on colon cancer development. Ex Fusobacterium nucleatum Butyrate producing bacteria

40. Mechanisms of Gut Microbiome Modulation Gut bacteria can influence cancer development through several mechanisms: Mutagenicity and DNA damage (e.g., E. coli with the PKS locus). Promoting cell proliferation by mimicking growth factor signaling.

41. Butyrate Paradox & Senescence Butyrate-producing bacteria are elevated in colorectal cancer patients. Butyrate has complex effects, including inducing senescence in epithelial cells. Senescent cells can promote tumor growth (e.g., mouse model study with senolytic drugs).

42. Microbiome and the immune system

43. Beyond the gut: systemic effects The gut microbiome can systemically influence cancer development and treatment in organs beyond the colon. Examples: Melanoma: Fecal transplants from therapy-responsive patients can improve outcomes. Cholangiocarcinoma: Gut dysbiosis impacts liver immunity via the portal vein.

44. Intratumoral microbiota Recent studies have revealed that distinct microbiomes exist within tumors themselves. Variations in the intratumoral microbiome are associated with specific cancer types and clinical features.

45. Intratumoral microbiota and cancer development Mouse models demonstrate a tumor-promoting influence of intratumoral microbiota, evidenced in studies of lung and pancreatic cancer. This effect may be linked to the bacteria's ability to drive tumor-promoting inflammation. Activate pattern recognition receptors on immune cells

46. Senescent cells

47. Cellular senescence: A state of irreversible cell cycle arrest triggered by various stressors. DNA damage, Oncogene Activation Initially viewed as protective against cancer, senescence can also promote tumor development.

48. Mechanisms of senescence induction Cellular senescence can be triggered by various stressors, including: DNA damage (e.g., from radiation, chemotherapy, or cellular metabolism) Oncogene activation Telomere shortening Other stressors (oxidative stress, disrupted metabolism)

49. Senescence-Associated Secretory Phenotype (SASP) Senescent cells release a complex mixture of factors (SASP) that can profoundly influence the tumor microenvironment and cancer cells themselves. SASP components include: Cytokines (e.g., IL-6, IL-8) Chemokines (e.g., CXCL8) Proteases (e.g., MMPs)

50. Senescence, Tumor Promotion, and Therapy Resistance The Senescence-Associated Secretory Phenotype (SASP) can drive hallmark capabilities, promoting tumor growth, metastasis, and therapy resistance. Examples: Promoting angiogenesis Suppressing anti-tumor immunity Therapy-induced senescence and tumor dormancy

51. Senescent Stromal Cells Stromal cells within the tumor microenvironment (TME) can also undergo senescence. Senescent stromal cells can significantly influence tumor behavior. Examples: Senescent fibroblasts and their role in field effects and immunosuppression. Potential tumor-promoting effects of senescent endothelial cells

52. Senescent cells, both cancer cells and those within the stromal compartment, significantly influence the tumor microenvironment (TME). Senescent cells should be considered a crucial component of tumor development and progression.

53. Expanding the Hallmarks of Cancer New research suggests potential additions to the current hallmarks of cancer framework: Cellular Plasticity as a distinct hallmark capability. Nonmutational Epigenetic Reprogramming and Polymorphic Microbiomes as enabling characteristics. Senescent Cells as a key TME component with tumor-promoting potential .