a Good prognosis Poor prognosis Metastasis Good prognosis

a. Good prognosis Poor prognosis Metastasis Good prognosis Metastatic variants Metastasis b. c. Good prognosis Poor prognosis Metastasis

a. Separate origins Normal tissue Poor prognosis b. Clonal progression BUT - are the tumors homogeneous even for primary tumor growth

CD 44+ / B 38. 1+ CD 24 lo Lin-

Lin- / CD 44+ / CD 24 lo Cells are tumorigenic They comprise minority of cells in tumor They don’t have a growth advantage

Lin- / CD 44+ / CD 24 lo cells are tumorigenic Sorting for ESA+ further enriches - only a few % of cells in tumor.

T 1 200 P 1 sorted P 2 T 2 1000 Lin- / CD 44+ / CD 24 lo cells regenerate the mixture of cell types thru 4 passages

Therefore tumors contain rare, self-renewing cells that are tumorigenic and can regenerate multiple cell types That is, tumor stem cells or tumor-initiating cells. Most cells in the tumor lack these properties. Therapy should be directed at the subset, not the majority.

Micrometastases Present in 30% of Br. Ca patients but only 50% eventually progress to clinically evident tumors within 5 years Are they a mix of rare malignant seeds and other non-malignant seeds? Or do they reflect seeding of a homogeneous set of premalignant cells with a uniform probability of forming frank tumors?

Good prognosis Stromal response Metastatic variants Poor prognosis Metastasis