Mustapha Abubakar

M.D., Ph.D.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, USA

Stadtman Investigator

PLCO (Learn more about this study)

2023-0058

Jun 12, 2023

Characterizing the role of disruptive changes in native stromal architecture and cell composition in the etiopathogenesis and natural history of multi-state colorectal and prostate cancers

Prevailing theories of multi-state carcinogenesis posit a linear sequence of changes, mostly epithelial, beginning from normal cells and culminating in the emergence of invasive carcinoma. Accordingly, etiologic and natural history studies of multi-state carcinogenesis to date have mostly focused on epithelial changes either as targets of carcinogenic insults arising from cumulative exposure to risk factors, or as markers of cancer risk and disease progression. However, accumulating body of research has shown that non-epithelial tissue components play crucial roles in multi-state carcinogenesis. In particular, stromal changes have been shown to impact the biology and clinical outcomes of several cancer types, including breast, colorectal, and prostate cancers. The role of the stromal microenvironment in the etiopathogenesis and natural history of these tumors is, however, poorly understood. In a recent work involving U.S-based women who donated normal breast tissue to the Susan G. Komen Tissue Bank (KTB), we found several risk factors for breast cancer to be associated with stromal-epithelial features in ways that were consistent with their breast cancer risk associations. In another study involving US-based benign breast disease (BBD) patients, we found a context dependent role of the stroma, to prevent or promote the risk of future invasive breast cancer development in patients with non-proliferative or proliferative BBD, respectively. In an ongoing follow-up study of over 10,000 subjects from seven study populations internationally, we comprehensively characterized stromal disruption phenotypes across the breast cancer continuum by using high-accuracy machine-learning algorithms on standard histological images, in conjunction with novel multiplex immunofluorescence staining of 10 markers. Our findings define, for the first time, a clear stromal pathway of multi-state carcinogenesis that links etiologic factors to stromal disruption, and the latter to the etiopathogenesis and natural history of phenotypically and clinically aggressive breast cancers. Here, we are proposing to extend this paradigm to other epithelial cancers (colorectal and prostate), with benign and/or precursor states that can be detected during screening. It is our hypothesis that distinct stromal disruption phenotypes may characterize colorectal and prostate carcinogenesis, providing the missing link into the etiopathogenesis and natural history of aggressive phenotypes of these cancers.