Mouse models of advanced spontaneous metastasis for experimental therapeutics

Abstract

An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models.

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…These features are not recapitulated by subcutaneously growing PDACs, which lack the abundant desmoplastic stroma and high interstitial pressure that limits blood vessel functionality in autochthonous (or orthotopic) tumors. Even orthotopic xenotransplant PDAC tumors growing in the pancreas are hypervascular in comparison to genetically engineered mouse models (GEMMs) and human PDACs (Olive et al., 2009); for other tumor types, however, orthotopic transplants may more accurately reflect the bona fide angiogenic and stromal components of the tumor microenvironment, and as such present an important experimental alternative to subcutaneous tumor xenografts (Francia et al., 2011). …”

“…Because metastatic disease represents the ultimate target of anticancer therapies, preclinical models that can recapitulate organ‐specific metastasis should be developed and employed to more realistically assay the therapeutic potential of candidate drugs. Orthotopic transplants (including PDX models) may enhance the incidence of distant metastatic spread compared with subcutaneous transplants (Derose et al., 2011), especially if the primary tumor is surgically removed to allow the development of macroscopic metastases from the disseminated tumor cells (Francia et al., 2011). Highly metastatic human tumor variants can also be generated through multiple rounds of in vivo growth of tumor cell lines in immunodeficient mice, each involving orthotopic tumor cell transplantation/growth/resection, and isolation of metastatic cells from the visceral organs (Francia et al., 2011; Kerbel et al., 1984).…”

“…Orthotopic transplants (including PDX models) may enhance the incidence of distant metastatic spread compared with subcutaneous transplants (Derose et al., 2011), especially if the primary tumor is surgically removed to allow the development of macroscopic metastases from the disseminated tumor cells (Francia et al., 2011). Highly metastatic human tumor variants can also be generated through multiple rounds of in vivo growth of tumor cell lines in immunodeficient mice, each involving orthotopic tumor cell transplantation/growth/resection, and isolation of metastatic cells from the visceral organs (Francia et al., 2011; Kerbel et al., 1984). This approach has been used to select highly metastatic tumor cell lines that may be representative of various human cancer types/subtypes (Francia et al., 2011); in some cases, genetic modification of the tumor cells was used to introduce relevant driver oncogenic mutations in the tumor cells (du Manoir et al., 2006).…”

“…Highly metastatic human tumor variants can also be generated through multiple rounds of in vivo growth of tumor cell lines in immunodeficient mice, each involving orthotopic tumor cell transplantation/growth/resection, and isolation of metastatic cells from the visceral organs (Francia et al., 2011; Kerbel et al., 1984). This approach has been used to select highly metastatic tumor cell lines that may be representative of various human cancer types/subtypes (Francia et al., 2011); in some cases, genetic modification of the tumor cells was used to introduce relevant driver oncogenic mutations in the tumor cells (du Manoir et al., 2006). However, this approach is not easily applicable to the derivation of patient‐specific tumor cell lines that can inform on treatment options for the individual, as the in vivo selection procedure is laborious and lengthy (Francia et al., 2011).…”

“…This approach has been used to select highly metastatic tumor cell lines that may be representative of various human cancer types/subtypes (Francia et al., 2011); in some cases, genetic modification of the tumor cells was used to introduce relevant driver oncogenic mutations in the tumor cells (du Manoir et al., 2006). However, this approach is not easily applicable to the derivation of patient‐specific tumor cell lines that can inform on treatment options for the individual, as the in vivo selection procedure is laborious and lengthy (Francia et al., 2011). …”