Cancer Biology Part 3 Cancer stem cells and

Cancer Biology (Part 3) Cancer stem cells and differentiation Metastasis Cancer types by organ of origin Yi Li Ph. D. Assistant Professor Lester and Sue Smith Breast Center & Department of Molecular & Cellular Biology Baylor College of Medicine date

Carcinoma: any of various types of malignant neoplasm derived from epithelial cells, chiefly glandular (adenocarcinoma) or squamous (squamous cell carcinoma); the most occurring kind of cancer Table 2. 1 The Biology of Cancer (© Garland Science 2007)

Sarcoma: a connective tissue neoplasm, usually highly malignant, formed by proliferation of mesodermal cells Table 2. 2 The Biology of Cancer (© Garland Science 2007)

Hematopoietic cancer Table 2. 3 The Biology of Cancer (© Garland Science 2007)

Stem cells • Self-renewal • Differentiate into all lineages in a tissue stem cell progenitor cell (transient amplifying cells) differentiated cells

Figure 12. 4 The Biology of Cancer (© Garland Science 2007)

From Hanahan & Weinberg 2000. Cell 100: 57 -70

Figure 11. 43 The Biology of Cancer (© Garland Science 2007)

Clonal Evolution of Cancer Figure 11. 12 The Biology of Cancer (© Garland Science 2007)

Cancer evolution Figure 11. 7 The Biology of Cancer (© Garland Science 2007)

Breast Cancer Evolution Normal ADH DCIS IBC Tracy Vargo-Gogola & Jeffrey M. Rosen (2007) Nature Reviews Cancer 7, 659 -672 Metastasis

Breast cancer subtypes (histopathology-based) • • • Invasive ductal carcinoma, NOS Invasive lobular carcinoma Inflammatory breast cancer Medullary carcinoma Mucinous (colloid) carcinoma Paget's disease of the breast Tubular carcinoma Metaplastic carcinoma Micropapillary carcinoma Adenoid cystic carcinoma

Hierarchical clustering of 115 tumor tissues and 7 nonmalignant tissues using the "intrinsic" gene set Fig 1. Hierarchical clustering of 115 tumor tissues and 7 nonmalignant tissues using the "intrinsic" gene set. (A) A scaled-down representation of the entire cluster of 534 genes and 122 tissue samples based on similarities in gene expression…. Branches corresponding to tumors with low correlation to any subtype are shown in gray. Sorlie et al. (2003) Proc. Natl. Acad. Sci. USA 100, 8418 -8423

Cancer Stem Cells

Fluorescence-activated cell sorting Figure 11. 13 The Biology of Cancer (© Garland Science 2007)

CD 34+/CD 38 - AML cells • As few as 5 x 103 can regenerate AML in NOD/SCID mice, whereas 5 x 105 CD 34+/CD 38+ cells did not • Can self renew. • Can differentiate into leukemic blasts • Contain the same surface markers found in normal hematopoietic stem cells.

Identification of breast cancer stem cells Figure 11. 14 a The Biology of Cancer (© Garland Science 2007) Al-Hajj et al. : PNAS, 100: 3983 -3988, 2003

Cancer stem cells exist in many cancers Brain Colon Head and neck Lung Prostate Pancreas

Cancer stem cells need not to arise from normal stem cells Bjerkvig et al. , 2005, Nature Rev Cancer. 5: 899.

Targeting cancer stem cells may be highly effective in treating cancer Reya et al. , (2001) Nature 414: 105 -111

Metastasis The appearance of neoplasms in parts of the body remote from the site of the primary tumor

Metastasis is the last step in cancer progression and is responsible for 90% of cancer deaths Figure 11. 10 The Biology of Cancer (© Garland Science 2007)

A primary tumor may disseminate through hematogenous or lymphatic vessels or by direct extension though serous cavities or subarachnoid or other spaces Pantel & Brakenhoff. 2004

Fidler 2003

Chambers et al. 2002

Figure 14. 42 The Biology of Cancer (© Garland Science 2007)

“seed and soil” theory of cancer spread Stephen Paget scrutinized more than 900 autopsy records of patients with different primary tumour. His analysis documented a non-random pattern of metastasis to visceral organs and bones. These findings indicated to Paget that the outcome of metastasis was not due to chance, but that certain tumour cells have specific affinity for the milieu of certain organs He concluded that metastases formed only when the seed and soil were compatible. “When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil. ” Stephen Paget (1855 -1926) Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571 -573 (1889).

In 1928, James Ewing challenged Paget's 'seed and soil' theory, and proposed that circulatory patterns between a primary tumor and specific secondary organs were sufficient to account for organspecific metastasis. Ewing, J. Neoplastic Diseases edn 6 (W. B. Saunders, Philadelphia, 1928). Chambers et a. Nature Reviews Cancer 2, 563 -572 (2002) Figure 14. 44 The Biology of Cancer (© Garland Science 2007)

Both blood flow patterns and seed–soil compatibility contribute to the ability of specific types of cancer to spread to various target organs. Leonard Weiss, 1992. Clin. Exp. Metastasis 10, 191 -199: Blood flow patterns explain metastasis in 2/3 of the tumortype–organ pairs among 16 primary tumor types and 8 target organs that were analyzed.

Organ-specific barriers to metastatic infiltration Nguyen et al (2009) Nat Rev Cancer 9: 274 -84.

Breast cancer Preferred sites of metastasis CXCR 4 CXCL 12/SDF-1 CCR 7 CCL 21

A model for the survival and emergence of latent disseminated tumor cells Nguyen et al (2009) Nat Rev Cancer 9: 274 -84.

Transition between epithelial and mesenchymal stats during cancer progression Polyak, Weinberg (2009) Nat Rev Cancer 9: 265 -73.

Klein (2009) Nat Rev Cancer 9: 302 -12.

Leaving home early Podsypanina et al, 2008, Science

Parallel progression Klein (2009) Nat Rev Cancer 9: 302 -12.

Tumor self-seeding Leung, Brugge (2009) Cell 139: 1226 -8.

Metastases resemble the corresponding primary tumors in expression profiles Figure 14. 52 b The Biology of Cancer (© Garland Science 2007)

Figure 14. 51 a The Biology of Cancer (© Garland Science 2007)

Figure 14. 51 b The Biology of Cancer (© Garland Science 2007)

The End

EMT at the interface between tumor epithelium and stroma Figure 14. 19 c The

Do these mets have corresponding primary tumors in these 64 samples? Figure 14. 51 a The Biology of Cancer (© Garland Science 2007)

Do this signature predict metastasis? ? ? Figure 14. 51 b The Biology of

• Does TG expression of CXCR 4 ligand lead to metastasis in sites that are otherwise not preferred. • Does CXCR 4 ligand knockout prevent metastasis to these preferred sites?