Tumorzelldissemination und Metastasierung beim gastro-intestinalen Karzinom: Mechanismen, Nachweis und Bedeutung

Zusammenfassung.

In Deutschland werden ca. ein Drittel der tumorbedingten Sterbefälle durch gastrointestinale Malignome verursacht. Die Therapieoption der ersten Wahl ist beim gastrointestinalen Karzinom die chirurgische Resektion entsprechend den chirurgisch-onkologischen Prinzipien nach möglichst früher Diagnosestellung. Während die Wahrscheinlichkeit für das Auftreten und die Häufigkeit eines Lokalrezidives mit durch den „Prognosefaktor” Chirurg beeinflusst wird, ist die Fernrezidivrate von über 30 % nach potenziell kurativer Resektion nach heutigem Kenntnisstand in erster Linie auf eine prä- bzw perioperative Tumorzelldissemination zurückzuführen. Diese früh aus dem primären Tumorverband herausgelösten Zellen sind mit konventionellen histopathologischen Verfahren und bildgebenden Staginguntersuchungen nicht nachweisbar, spielen jedoch bei der Metastasierungskaskade eine entscheidende Rolle. Im Sinne eines erweiterten Stagings ist heute jedoch deren Nachweis in verschiedenen Körperkompartimenten mittels immunzytochemischer oder molekularbiologischer Verfahren möglich, wobei eine Vielzahl von Studien deren klinische Relevanz und unabhängige prognostische Bedeutung belegt hat. Die gelegentlich jahrelange Latenzphase zwischen Resektion des Primärtumors und der Manifestation von Fernmetastasen mag teilweise durch die Beobachtung erklärt sein, dass die Mehrzahl der disseminierten Tumorzellen mitotisch inaktiv ist („dormancy”). Gleichzeitig könnte dies die eingeschränkte Wirksamkeit zellzyklusabhängiger, antiproliferativer Chemotherapeutika bedingen. Antikörpervermittelte, proliferationsunabhängige adjuvante Therapieverfahren scheinen hier eine neue, nebenwirkungsarme Therapieoption darzustellen, zumal mikrometastatische Tumorzellen leicht für intravenös applizierte Chemotherapeutika, Makromoleküle und immunkompetente Effektozellen zugänglich sind. Zusätzlich könnte die Analyse der Tumorzelldissemination im Verlauf einer systemischen Therapie auch als Surrogatmarker für deren Effizienz Verwendung finden.

Tumor cell dissemination and metastasis in gastrointestinal cancer: Mechanisms, detection and clinical relevance.

In Germany, about one third of tumor-related deaths are caused by gastrointestinal carcinomas. Complete resection according to surgical and oncological principles after early diagnosis is the therapeutic approach of choice. While the incidence of local recurrence after complete resection is considerably affected by the skills of the surgeon, distant relapse in up to 30 % is mainly due to pre- and/or perioperative tumor cell dissemination. Conventional histopathological methods and current radio-imaging techniques are unlikely to detect these cells that have left the primary tumor site and play a crucial role in the formation of distant metastasis. Immunocytochemical and molecular methods have made individual disseminated tumor cells detectable in various compartments of a patients organism and their presence is increasingly considered as a clinically relevant and independent prognostic factor. The majority of these tumor cells appears to be nonproliferating (“dormancy”) which may explain the limited efficacy of cell-cycle dependent antiproliferative chemotherapeutic agents. This mitotic inactivity could also account for the latency period between resection of the primary tumor and the manifestation of distant metastasis. In this context, antibody mediated therapeutic approaches directed against quiescent disseminated tumor cells seem to be of clinical relevance, particularly since isolated micrometastatic cells are easily accessible for intravenously applied therapeutic agents, macromolecules and immunologic effector cells. In addition, the monitoring of circulating cancer cells in the course of a systemic therapy could be useful in determining the efficacy of new therapeutic agents at an early point.

Schlüsselwörter:

Tumorzelldissemination - Minimal residual disease - Knochenmark - Lymphknoten - Prognose - Metastasierung

Key words:

Tumor cell dissemination - Minimal residual disease - Bone marrow - Lymph node - Prognosis - Metastasis

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