The Perioperative Period is an Underutilized Window of Therapeutic Opportunity in Patients With Colorectal Cancer

Bij, Gerben J. van der; Oosterling, Steven J.; Beelen, Robert H.J.; Meijer, Sybren; Coffey, J. Calvin; Egmond, Marjolein van

doi:10.1097/sla.0b013e3181a3ddbd

Cited by 197 publications

(159 citation statements)

References 95 publications

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“…Other issues of possible importance are the immunological stress and inflammatory responses triggered by surgery along with the stimulation of cell proliferation needed for wound healing [15,16]. Little is known how the surgical trauma affects the risk of distant metastases and if this could be modulated by preoperative chemotherapy [17,18]. In the present study a neoadjuvant treatment with Pemetrexed (Alimta), a more recent TS inhibitor, was assessed for feasibility in rectal cancer.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer

Derwinger

Kodeda

Swartling

et al. 2011

European Journal of Surgical Oncology (EJSO)

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AimThe aim was to assess the feasibility of preoperative chemotherapy and possible tumour response using Pemetrexed (Alimta) in rectal cancer. MethodThe study was a prospective, non-randomized, single centre phase I/II feasibility trial. 37 patients with resectable rectal cancer were recruited and given three 3 week cycles of preoperative Pemetrexed therapy. Tumour size and stage were assessed by MRI scans before and after chemotherapy. Treatment tolerability and response such as changes in tumour size and symptoms were assessed. ResultsAll patients completed the chemotherapy. Whilst mild side effects were frequent (grade 1, 34/37), the risk of severe effects was limited (grade 3 or 4, 4/37). Overall, there was a significant reduction in tumour size (p<0.001). By RECIST criteria, one patient had tumour progression, 23/36 had stable disease and 12 patients had a response of up to 65%. There was also a significant decrease in the number of pretreatment symptoms (p<0.018) including reduction of bleeding and diarrhoea/constipation. ConclusionPreoperative (Neoadjuvant) treatment with Pemetrexed was feasible in studied patients. Serious side effects were limited and a radiological tumour response or stable disease was seen in a majority of patients.

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Section: Discussionmentioning

confidence: 99%

A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer

Derwinger

Kodeda

Swartling

et al. 2011

European Journal of Surgical Oncology (EJSO)

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“…Activation of the immune response following surgery is fundamental for reparative processes but evidence suggests that it may also enhance the risk of tumor recurrence and systemic metastases (4,5). (5)During hepatic surgery, the liver is routinely subjected to injury due to ischemia resulting from the interruption of the hepatic blood supply that is often necessary to control blood loss.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress

Tohme

Yazdani

Simmons

et al. 2017

HPB

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Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether as a result of its ability to ensnare moving cells NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice, through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase (PAD4), which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophilderived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. HHS Public Access

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“…Only after we remove the primary tumor do we see a significant effect on lung metastases, suggesting that the HIF pathway is stimulated by surgery, perhaps because surgery activates the wound response. These observations are consistent with what has been reported in the clinic, that surgery can induce cancer metastasis [290]. However, the distinct lack of a difference in phenotype between WT and KO PyMT cells when studying metastasis using the tail vein model, suggests that HIF-1α plays a more pronounced role in the early stages of metastasis in this model.…”

Section: The Hifs Promote Tumor Metastasissupporting

confidence: 81%

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

Peacock¹

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DEDICATION ABSTRACTHypoxia is a hallmark of most solid tumors. In response to hypoxic stress tumor cells adapt by regulating survival, metabolism and angiogenesis. The heterodimeric Hypoxia-Inducible Factor (HIF) transcription factors are the master regulators of this response. HIFs play key roles in many critical aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, invasion, metastasis and resistance to radiation therapy and chemotherapy. Overexpression of HIF-1α and HIF-2α has been documented in multiple human cancers and HIF-1α protein is over-expressed in ~30% of primary breast tumors and ~70% of metastases, which independently correlates with poor prognosis and decreased survival in patients. A precise role for HIF-2α in breast cancer is still being elucidated.Our lab has established primary mammary tumor epithelial cells (MTECs) from late stage carcinomas originating in PyMT+; Hif1a floxed mice. These MTECs were exposed to either Adenovirus-beta-gal or -Cre to create wild-type (WT) and knockout (KO) cells, respectively. Deletion of HIF-1 activity reduced primary tumor growth by ~60% and the formation of lung macrometastases originating from mammary fat pad tumors by >90%. In addition, deletion of Hif1a reduced mammary tumorsphere formation efficiency (TSE) in vitro and tumor initiating cell (TIC) frequency in vivo. In contrast, in triple negative models of breast cancer, knockdown of HIF1A had the opposite phenotype, increasing TSE in vitro and increased primary mammary tumor growth in vivo. ITGA6 (CD49f) was identified as one HIF-1α-dependent cancer stem cell marker that enriches for both primary mammary tumor growth and metastasis to the lung. Microarray profiling conducted to identify genes differentially expressed between PyMT WT and KO cells and end-stage WT and KO tumors revealed several genes that were down-regulated in both data sets in response to deletion of Hif1a. One mRNA of particular interest, creatine kinase brain isoform (Ckb) was down-regulated in KO cells >100 fold and >2 fold in end-stage tumors. Transplantation of Ckb knockdown (KD) PyMT cells to the mammary fat pad delayed initiation of palpable tumors by >30 days. When cells were introduced into the circulation via tail vein injection, 20% of mice injected with Ckb KD cells developed lung metastases whereas 100% of mice injected with WT cells developed metastases. Likewise, when mice injected with WT PyMT cells were treated daily with a CKB chemical inhibitor, cyclocreatine (cCr), lungs of vehicle treated (saline) mice were almost completely covered with surface metastases, while lungs of cCr treated mice contained very few metastases.Overall, our data show that HIF-1α strongly promotes mammary tumor initiation, progression and metastasis, in part through regulation of TIC activity. Metastasis is the major cause of mortality in breast cancer patients. Further characterization of the distinct roles of HIF-1α versus HIF-2α in breast cancer and metastasis, and genes downstream of the HIFs, suc...

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The Perioperative Period is an Underutilized Window of Therapeutic Opportunity in Patients With Colorectal Cancer

Cited by 197 publications

References 95 publications

A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer

A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer

Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

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