Modeling Multiscale Necrotic and Calcified Tissue Biomechanics in Cancer Patients: Application to Ductal Carcinoma In Situ (DCIS) - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 343

1 Introduction

At its most basic level, cancer is a disease of uncontrolled cell proliferation: cancer
cells, either through mutations or epigenetic alterations, overexpress oncogenes
and underexpress tumor suppressor genes (TSGs). Consequently, the cells enter
into and progress through the cell cycle more often than they should and disregard
apoptotic signals, resulting in a net increase in proliferation and aberrant tissue
growth. (See recent cancer biology tutorials for modelers and physical scientists,
such as [ 50 , 52 , 53 ]). Accordingly, cell proliferation and apoptosis, along with
genetic mutations and epigenetic alterations in genes controlling these processes,
have been major foci of both basic cancer research and modeling. Most cancer
therapies attempt to manipulate these processes either by cytostatic (suppressing
entry to or progression through the cell cycle) or cytotoxic (inducing apoptosis:
programmed cell death) mechanisms. For example, chemotherapy agents such as
doxorubicin are considered to be cytotoxic [ 10 ]; therapies that target hormone-
addicted cells (e.g., tamoxifen in estrogen-driven breast cancer) are considered to
be cytostatic [ 74 ].

Key biological and clinical terms
Basement membrane (BM) ( 100 nm) thick plasto-viscoelastic membrane

separating epithelial and stromal tissues

Extracellular matrix (ECM) Fibrous supportive scaffolding in stromal tissue

Oncogene A growth-promoting gene

Tumor suppressor gene (TSG) A growth-inhibiting gene

Apoptosis Well-regulated, programmed cell death

Anoikis Apoptosis due to loss of attachment to the BM

Necrosis Disordered cell death

Oncosis Cell death at the start of (or preceding) necrosis,

marked by rapid cell swelling

Adenosine triphosphate (ATP) The immediate product of aerobic cell metabolism,

and the ''currency'' of cell energy

(Apoptotic) caspase Proteases responsible for degrading intracellular

proteins during apoptosis

In situ carcinoma Cancer contained by an intact BM

Ductal carcinoma in situ (DCIS) An in situ precursor to invasive ductal breast cancer

Comedonecrosis Necrotic tissue filling the lumen of a gland, most

typically with intraductal breast cancers

Invasive ductal carcinoma (IDC) An invasive breast cancer derived from ductal cells

Van Nuys Prognostic Index (VNPI) A system for evaluating DCIS and guiding treatment

Necrosis—the disorderly death of cells due to rapid injury or energy deple-
tion—has seen less attention in basic cancer research and computational modeling.
Indeed, cancer apoptosis publications outnumber cancer necrosis in PubMed by
over three to one after excluding tumor necrosis factor (TNF) citations that are