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Most cancer-related deaths are due to drug resistance and/or metastatic spread of tumour cells. These two properties of cancer cells have often been viewed--and studied--as separate processes. However, increasingly, this [...]

The words 'side effect' in cancer treatment usually refer to toxicities caused by drugs on host organ tissues and cells. With respect to chemotherapy, for example, they include myelosuppression, hair [...]

We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse models of cancer involving treatment of advanced metastatic disease. Historically, mouse cancer therapy models have been dominated by treating established primary tumors or early stage low volume microscopic disease. Treatment of primary tumors is also almost always the case when using genetically engineered mouse models (GEMMs) of cancer or patient-derived xenografts (PDXs). Studies using such models, and others including transplanted cell lines, often yield highly encouraging results which are seldom recapitulated in the clinic, especially when assessed in randomized phase III clinical trials. While there are likely many different reasons for this discrepancy, one is likely the failure to recapitulate treatment of advanced visceral metastatic disease in mice. With this gap in mind, we have developed a number of models of metastatic human tumor xenografts (and more recently, of mouse tumors in syngeneic immunocompetent mice). A pattern of response we have observed with various targeted agents, e.g. VEGF pathway targeting antiangiogenic drugs or trastuzumab, is effective when treating primary tumors in contrast to a complete or severely reduced lack of such efficacy when treating advanced metastatic disease. Interestingly, an exception to this pattern has been observed using various continuous low-dose metronomic chemotherapy regimens, where counterintuitively, superior responses are observed in the metastatic setting, as well as superiority or equivalence of metronomic chemotherapy over standard maximum tolerated dose (MTD) chemotherapy, with lesser toxicity. The basis for these encouraging results may be related to the multiple mechanisms responsible for the anti-tumor effects and longer duration of metronomic chemotherapy regimens made possible by lesser toxicity. These include antiangiogenesis, stimulation of the immune system, stromal cell targeting in tumors, and possibly direct tumor cell targeting, including targeting cancer stem cells (CSCs). In addition, metronomic chemotherapy regimens minimize or even eliminate the problem of chemotherapy-induced host responses that may actually secondarily promote tumor growth and malignancy after causing an initial and beneficial anti-tumor response. We suggest that future preclinical studies of metronomic chemotherapy should be concentrated in the following areas: i) further comparative assessment of anti-tumor efficacy in primary vs metastatic treatment settings; ii) rigorous comparative assessment of conventional MTD chemotherapy vs metronomic chemotherapy using the same agent; iii) assessment of potential predictive biomarkers for metronomic chemotherapy, and methods to determine optimal biologic dose and schedule; and iv) a further detailed assessment of the potential of different chemotherapy drugs administered using MTD or metronomic regimens on stimulating or suppressing components of the innate or adaptive immune systems. [ABSTRACT FROM AUTHOR]

Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns ( HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]