Growth and metastasis of human breast cancers in athymic nude mice

Abstract

To evaluate critically the merit of utilizing a wound model for growing human tumors, a series of increasingly difficult human tumor types were tested for growth at sites of trauma in athymic nude mice. In vitro tumor lines as well as fresh tumors from the breast, colon, rectum, lung, and a metastasis from an unknown primary were intraperitoneally injected into mice subjected to intra-abdominal organ injury. Successful xenografts were obtained from nine of 10 cell lines and 14 of 24 fresh tumors. The latter included five of six (83%) colon cancers, one lung tumor, metastatic tumor of unknown primary, three of four (75%) metastatic breast cancers and four of six (67%) estrogen receptor (ER)-negative breast primary tumors. Six ER-positive breast tumors tested failed to grow in mice without estrogen supplementation. Xenografts from two breast, two colon and the lung cancers formed spontaneous metastases and all xenografts tested were able to yield serial transplants in the surgical wound model. Histologically, all xenografts and their metastases were identical to their respective donor tumors. Transplantability in mice without exogenous estrogen supplementation was linked to the absence of estrogen and progesterone receptors in breast tumors. Transplantability of the cell lines was associated with the expression of cell surface receptors for fibronectin and hyaluronic acid. Receptors for other extracellular matrix components, namely, laminin, vitronectin, collagen, fibrinogen or von Willebrand factor were not associated with transplantability. These results demonstrate that a large proportion of human tumors, including the breast tumors, can be successfully xenografted into athymic mice by providing them with a healing wound environment, and that such xenografts grown at ectopic sites exhibit metastatic ability.

A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-Derived Human Breast Cancer Xenograft Models

“…Fifteen patients yielded a stable xenograft (21.4% stable take rate), an approximately 8-fold increase above baseline, and consistent with recently published studies [1, 2, 5, 6, 8-12]. Stable lines represented 12 “triple negative” patients (Table 2), as well as two ER-PR-HER2+ patients (lines BCM-3143/3104 and BCM-3963/4169), and one ER+PR+HER2− patient (line BCM-5097).…”

“…Historically, stable take rates for xenografts were low (~10%, or less), but have improved in more recent studies [1, 2, 5, 6, 8-10, 34-41]. Our stable take rate under condition 2 (estradiol supplementation in SCID/Bg mice) was ~21%, with a statistically similar take rate observed in NSG mice (~19%).…”

“…patient-derived xenografts (PDX) models, or “tumorgrafts”) as experimental models met with limited success [1, 2, 5, 6, 8-12], with typical rates of stable transplantation being 10% or less. Most of these attempts used athymic (“nude”) or NOD/SCID (non-obese diabetic/severe combined immunodeficiency disorder) mice, which lack B- and T-cell function but retain innate cellular immunity (natural killer (NK) cells, macrophages etc.)…”

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

“…Further, once established ER expression can be lost over the course of passaging from mouse to mouse (e.g. [68,57,164], Miragaya et al unpublished), though many current studies have not shown this behavior. These difficulties are offset, in part, by the fact that ER+ cancers account for approximately 75% of all breast cancers, thus offering more opportunities to make successful PDX models.…”

A new hypothesis for the cancer mechanism

“…WOWH mechanism gives another explanation for this phenomenon: there is no correct wound molecular environment in the normal mouse for transplanted cancer cells to respond, while nude mice are partial wounded bodies that some cancer cells with the right activated genes may respond to them. Due to the partial wounded bodies, nude mice do not provide molecules that are suitable for all transplanted cancer cell growth, but the tumor growth may be promoted by providing a wound environment [92, 93]. The use of Matrigel (BD Biosciences) in the transplanted tumor model [94] is an example of such a situation since TGF-β [38], FGF [38], EGF [95], insulin-like growth factor-1 [95], platelet-derived growth factor (PDGF) [96], and nerve growth factor [97] in Matrigel are all actively expressed factors in wounds and they all can activate oncogenes, such as Src [98–103], for cancer progress.…”