Brief Urology article  12 Dec.2013

1.Tanya Stoyanovaa,

2.Aaron R. Cooperb,

3.Justin M. Drakea,

4.Xian Liuc,

5.Andrew J. Armstrongd,

6.Kenneth J. Pientae,

7.Hong Zhangf,

8.Donald B. Kohna,g,h,

9.Jiaoti Huangf,g,h,

10.Owen N. Wittea,c,g,h,i,1, and

11.Andrew S. Goldsteinc,g,h,j,1

aMicrobiology,mmunology and Molecular Genetics, bMolecular Biology Interdepartmental Ph.D. Program, cDepartments of Molecular and Medical Pharmacology, fPathology and Laboratory Medicine, gJonsson Comprehensive Cancer Center, David Geffen School of Medicine, hEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, iHoward Hughes Medical Institute, and jDepartment of Urology, University of California, Los Angeles, CA 90095; dDuke Cancer Institute, Duke University Medical Center, Durham, NC 27710; and eBrady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD 21287

The relationship between the cells that initiate cancer and the cancer stem-like cells that propagate tumors has been poorly defined. In a human prostate tissue transformation model, basal cells expressing the oncogenes Myc and myristoylated AKT can initiate heterogeneous tumors. Tumors contain features of acinar-type adenocarcinoma with elevated eIF4E-driven protein translation and squamous cell carcinoma marked by activated beta-catenin. Lentiviral integration site analysis revealed that alternative histological phenotypes can be clonally derived from a common cell of origin. In advanced disease, adenocarcinoma can be propagated by self-renewing tumor cells with an androgen receptor-low immature luminal phenotype in the absence of basal-like cells.

These data indicate that advanced prostate adenocarcinoma initiated in basal cells can be maintained by luminal-like tumor-propagating cells. Determining the cells that maintain human prostate adenocarcinoma and the signaling pathways characterizing these tumor-propagating cells is critical for developing effective therapeutic strategies against this population.

Tumors that arise from a given tissue in the body exhibit heterogeneity with respect to their molecular alterations, biological behavior, and response to therapy .Such variation presents a serious challenge for clinical cancer management. In many organ sites, tumors have been classified into subtypes based on their molecular and histological features .Subtypes of cancer can reflect distinct states of differentiation within a given tissue, leading Visvader and coworkers to propose that different epithelial tumor subtypes can arise from transformation of distinct cells of origin with different developmental potential .Functional studies in the mouse mammary gland and mouse lung support this model .However, there is limited functional evidence for such a mechanism in human epithelial cancer.

Several recent studies using mouse models have revealed that the same phenotypic cell that initiates cancer can be responsible for tumor maintenance or propagation. Lgr5+ intestinal stem cells can initiate and maintain murine intestinal adenomas .In mouse models of skin cancer, hair follicle bulge stem cells can serve as target cells for transformation and CD34+ cells resembling their normal bulge stem cell counterpart are capable of propagating the disease as a cancer stem cell population .Mouse models of breast cancer demonstrate that tumors can arise from the transformation of luminal cells ,and recent studies using human tumor samples indicate that breast cancer can also be propagated by luminal-like cells .In most human epithelial cancers it has not been determined whether the cell types that give rise to cancer are also capable of maintaining advanced disease.

The predominant histological subtype of prostate cancer is acinar-type adenocarcinoma ,with features of luminal secretory cells, rare neuroendocrine cells, and an absence of basal cells. A number of less common histological variants are found in prostate cancer, including small cell carcinoma and squamous cell carcinoma.

Both of these variants are associated with poor prognosis, aggressive disease, and resistance to hormonal therapy (androgen deprivation and/or androgen receptor blockade) .Small-cell carcinoma is characterized by proliferating neuroendocrine cells and loss of p53 .Squamous cancers have features of basal cells and can occur either in the context of adenocarcinoma or alone as squamous cell carcinoma .Based on their different phenotypes and response to hormonal therapy, different histological variants of prostate cancer are predicted to arise from distinct cells of origin .

The relationship between the cells that initiate and maintain human prostate adenocarcinoma is not known. Naïve human prostate basal cells can initiate acinar-type adenocarcinoma in response to oncogenic stimulation .Consistent with these findings, basal cells from the BPH-1 human prostate cell line can initiate human prostate cancer in response to combined estrogen and testosterone treatment .These collective data suggest that human prostate tumors may set aside a subset of basal cells within the tumor to ensure continuous production of malignant luminal-like cancer cells.

 

Human prostate cancer cells with a basal phenotype have been reported to produce luminal cancer progeny in vitro .Using cell lines that were originally derived from human prostate tumors, it was shown that basal cell marker CD44 enriched for tumor-propagating cells in the absence of differentiated luminal cell markers .A recent study demonstrates that advanced chemotherapy-resistant prostate cancer is maintained by cells lacking basal or luminal cytokeratins (19). No study has defined the role of basal or luminal-like cells isolated directly from primary human prostate cancer in tumor propagation.

In the present study, we use a tissue-regeneration model of human prostate cancer to determine whether the cells at the origin of prostate cancer are continually required to maintain the disease as tumor-propagating cells. Benign cell populations isolated from primary human prostate tissue were first tested for their susceptibility to transformation by defined oncogenes.

In the resulting tumors, cancer cell populations were further transplanted to define the cells capable of propagating the disease. Tumors driven by expression of oncogenes Myc and myristoylated/activated AKT (myrAKT) initiating in basal cells exhibit features of both adenocarcinoma and squamous cell carcinoma with different signaling pathways characteristic of each histological pattern. eIF4E-driven protein translation pathway is elevated in adenocarcinoma, whereas activation of beta-catenin is associated with squamous differentiation in experimental and clinical human prostate cancer. Using lentiviral integration site analysis, we determined that alternative histological phenotypes of prostate cancer can arise from a clonal cell of origin. Adenocarcinoma can be serially propagated by cells with a luminal phenotype.

Our results indicate that cancer initiated in basal cells can evolve to adenocarcinoma maintained by luminal-like cells.

Copyright © 2013 National Academy of Sciences.