Meeting the biologic challenge of colorectal metastases.

Division of Surgical Oncology, Landmark Medical Center, Woonsocket, RI, USA, .
Clinical and Experimental Metastasis (Impact Factor: 3.73). 10/2012; DOI: 10.1007/s10585-012-9517-x
Source: PubMed

ABSTRACT An overview of colorectal cancer discussed (Philip Paty) the good outcome after primary management with local control in 90-95 % of colon and 85 % in rectal cancer patients with major progression to metastases and to death related to hematogenous dissemination. The major disease pathways include the APC, aneuploid pathway involving mutations of P53, KRAS, SMAD 4, or the CMP/MSI pathway, mismatched repair defect as characterized by Lynch syndrome, the major hereditary form which may also have KRAS and P53 mutations. The common sporadic colorectal cancers are MS1 high, with many patients having BRAF and KRAS mutations. The sentinel node biopsy in colorectal cancer surgery may provide more definitive staging and perhaps modification of the extent of resection with better outcome as suggested by Dr. Saha. The identification of sentinel lymph nodes outside of the planned bowel resection may increase the resection biologically indicated by the sentinel lymph node location leading to better outcome. In a small study by Dr. Saha, the operation was enhanced in 21 % by extending the length of bowel resection, which increased node recovery to 18.5 nodes versus 12 nodes with the more conventional resection, increasing nodal recovery, and positivity to 60 % with reduction to five year recurrence rate to 9 % versus 27 % with the conventional resection. A new (Swiss) technique for pathologic node examination, the OSNA (the One Step Nucleic Acid diagnostic system), was presented which demonstrated increased detection of micro-metastases in a focused pathology study of 22 patients (Zuber) to 11 out of 15 patients versus the 7 micro-metastases identified by the standard single slide per node, and compared to 14 out of 15 with an intensive multi-slide technique. This suggests value in pursuing OSNA study by other centers with relevant clinical trials to establish its true value. An analysis of liver resection for metastatic colorectal cancer (CRC) emphasized the value of 10-year follow-up (DeAngelica). The 10-year survival of 102 patients among 612 patients was 17 % (Memorial Sloan Kettering data). At the five-year point 99 of 102 survivors were NED and 86 have been free of disease since the resection. The usual five-year figure after hepatic resection reveals that one-third of five-year survivors die from recurrence of distant disease suggesting the value of longer term follow-up in these patients. An additional question reviewed related to the role of neoadjuvant systemic chemotherapy (with response rates in the 50 % range) to produce down staging of the hepatic metastases and allow one to retrieve these patients with possible residual disease. In a series of 116 patients who had hepatic resection of CRC metastases in presence of regional node metastases, post neoadjuvant chemotherapy (normally not candidates for resection) these patients were demonstrated to have a 95 % recurrence at median time of 9 months. This raises a cautionary note to the literature report of five-year survivals in the 20-30 % range for hepatic metastases in presence of extra hepatic disease. Such may reflect patient selection rather than a true measure of the biology of disease, and warrant clinical trial evaluation. Lastly, regional therapy and overall systemic therapy were addressed by Dr. Kemeny. The CALGB study of hepatic artery infusion (HAI) with FUDR, dexamethasone versus 5FU leucovorin showed an overall survival of 24.4 months with HAI versus 20 months with systemic therapy (P = 0.0034). An adjuvant trial of HAI at MSK in 156 patients showed an overall survival benefit at 2 year and recent long term 10yr follow-up showing a significant overall survival of 41 % with HAI versus 27 % with systemic therapy (5FU leucovorin). In the neoadjuvant Nordlinger trial for hepatic metastases, there was a significant outcome differences-the preoperative therapy group had 9.2 % increase of progression free survival versus the surgery alone group which suggests the value of combining neoadjuvant surgery in good risk liver resection candidates. Conclude the final lesson from this well presented mini symposium confirms the need for continued evaluation of the numerous discussion points by clinical trial.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims: The aim of this study is to investigate the clinicopathological and prognostic values of miR-149 expression and its roles in colorectal cancer (CRC) progression. Methods: qRT-PCR was performed to detect miR-149 expression in CRC cell lines or tissues. Also, the clinical significance of miR-149 expression was investigated. The study further explored whether miR-149 inhibits migration and invasion of CRC cells by targeting the mammalian Forkhead Box M1 (FOXM1). Results: miR-149 was significantly downregulated in CRC tissues, and low miR-149 expression was observed to be significantly correlated with lymph node or distant metastasis and advanced TNM stage of CRC patients. Patients with low miR-149 expression showed poorer prognosis than those with high miR-149 expression, and multivariate analyses indicated that status of miR-149 expression might be an independent prognostic factor. Gain- and loss - of - function assays indicated that miR-149 significantly inhibited growth, migration and invasion of CRC cells by targeting FOXM1. Furthermore, FOXM1 was significantly uiregulated in CRC tissues and inversely correlated with miR-149 expression. Conclusions: mR-149 was an independent prognostic factor and could inhibit migration and invasion of CRC cells, at least partially by targeting FOXM1. © 2015 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 01/2015; 35(2):499-515. DOI:10.1159/000369715 · 3.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the fact that new treatment regimes have improved overall survival of patients challenged by colorectal cancer (CRC), prognosis in the metastatic situation is still restricted. The Bcl-2 family of proteins has been identified as promising anti cancer drug target. Even though small molecules targeting Bcl-2 proteins are in clinical trials, little is known regarding their effects on CRC. The aim of this study was to preclinically investigate the value of ABT-737 and Obatoclax as anticancer drugs for CRC treatment. The effects of the BH3-mimetics ABT-737 and Obatoclax on CRC cells were assessed using viability and apoptosis assays. Wound healing migration and boyden chamber invasion assays were applied. 3-dimensional cell cultures were used for long term assessment of invasion and proliferation. Clinically relevant concentrations of pan-Bcl-2 inhibitor Obatoclax did not induce cell death. In contrast, the BH3-mimetic ABT-737 induced apoptosis in a dose dependent manner. Obatoclax caused a cell line specific slowdown of CRC cell growth. Furthermore, Obatoclax, but not ABT-737, recovered E-Cadherin expression and led to impaired migration and invasion of CRC cells. The proliferative capacity and invasiveness of CRC cells was strikingly inhibited by low dose Obatoclax in long term 3-dimensional cell cultures. Obatoclax, but not ABT-737, caused a G1-phase arrest accompanied by a downregulation of Cyclin D1 and upregulation of p27 and p21. Overexpression of Mcl-1, Bcl-xL or Bcl-2 reversed the inhibitory effect of Obatoclax on migration but failed to restore the proliferative capacity of Obatoclax-treated CRC cells. The data presented indicate broad and multifaceted antitumor effects of the pan-Bcl-2 inhibitor Obatoclax on CRC cells. In contrast to ABT-737, Obatoclax inhibited migration, invasion and proliferation in sublethal doses. In summary, this study recommends pan-Bcl-2 inhibition as a promising approach for clinical trials in CRC.
    PLoS ONE 09/2014; 9(9):e106571. DOI:10.1371/journal.pone.0106571 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The tumour microenvironment (TME) represents a dynamic network that plays an important role in tumour initiation, proliferation, growth, and metastasis. Cell behaviour may be regulated by interplay of molecular interactions involving positive and negative reinforcement as well as a high level of cross-talk, which determines this system. Additionally, cancer involves cell proliferation, its malignancy defined by the tumour's ability to break down normal tissue architecture and by a dynamic process of invasion and metastasis. The metastatic cascade is regulated by a chain of molecular steps which triggers the progression of the developing cancer cell in the primary tumour into a number of transformations, leading to invasion and proceeding to metastases. Tumour-associated macrophages (TAMs) play a key-role in the progression from inflammatory conditions to cancer; TAMs are also capable of infiltrating the tumour microenvironment. Furthermore, myeloid-derived suppressor cells (MDSCs), a population of inhibitory immune cells, have been reported to increase in various cancer types, although characterising human MDSCs remains difficult, as their phenotype is quite variable. The future of cancer treatment is likely to involve creating more drugs that target these elements as well as others. An overview of the tumour's microenvironment is, therefore, presented in this paper, focusing on the metastatic pathways of primary colorectal cancer to the liver.
    Cancer Microenvironment 10/2014; DOI:10.1007/s12307-014-0155-5