Japanese Journal of Clinical Oncology Advance Access originally published online on January 29, 2009
Japanese Journal of Clinical Oncology 2009 39(3):192-194; doi:10.1093/jjco/hyn154
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© The Author (2009). Published by Oxford University Press. All rights reserved
Acute Inflammation and Micrometastasis Proliferation: A Fissure in the Uniformitarian Façade of Cancer
Haematology and Medical Oncology Department
Hospital Universitario Morales Meseguer
Calle Marqués de los Vélez sin número
30008 Murcia
Spain
E-mail: alberto.carmonabayonas{at}gmail.com
The principle ‘Natura non facit saltum’ attributed to Carl Linnaeus in the eighteenth-century had a deep influence in the current perception of natural processes, including some medical issues. In particular, geology, evolution and mass extinctions were once considered the tireless work of slow, gradual and continuous processes. That conception was called uniformitarianism and was defended by Lyell, the eminent nineteenth-century geologist. In contrast, George Cuvier believed that cataclysms and natural disasters disrupted the uniform rhythm of progressive evolution. Likewise, the predominant opinion implied that tumor progression did not make leaps, since cancerous cells proliferated and thrived without rapid skips and jumps. Gompertzian models are somehow a reminiscence of these thoughts. They are based on the idea that tumors always have to grow, since all the malignant cells have homogeneous capacities. One of the problems of these models is the inability to explain late relapses, which have been observed until 30 years after the resection of the primary tumor (1).
Once considered the innocent bystander of tumorogenesis and metastatic processes, it has now become clear that the microenvironment plays an important role in tumor cell growth and progression. The complex relationships between chronic inflammation and carcinogenesis have been extensively investigated. However, until recently, there was not much information about acute inflammation and tumorogenesis including micrometastasis proliferation. Thus, most oncologists have endorsed Lyell's conception and uniformitarianism.
In this respect, I comment on an anecdotal and extreme pattern of relapse that illustrates and challenges this paradigm. A 58-year-old patient with C2 Astler-Coller (pT3N2M0) rectal adenocarcinoma was diagnosed in 2002. The most remarkable medical antecedent was a jaw fracture 12 years earlier, which required maxillofacial surgery. He was also a heavy smoker having chronic bronchitis criteria. Thus, this patient was at high risk for disseminated micrometastasis seeding. He underwent low anterior resection and adjuvant chemoradiotherapy with 5-fluorouracil (200 mg/m2 daily), and further chemotherapy with the Mayo Clinic schedule (5-FU bolus 425 mg/m2 plus LV 20 mg/m2 daily for 5 days, repeated every 4 weeks) for six cycles. He was disease-free until January 2005, when a bone metastasis involving the first metatarsal was detected (Fig. 1). Three months earlier, he fractured this bone when transporting the door of a large wardrobe. As further evolution suggested, this event was a clear molecular catastrophe according to Cuvier's sense.
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Because of the traumatic antecedent and the rarity of the location, a bone metastasis was not initially suspected. Nevertheless, the fracture did not heal in the subsequent weeks, despite the immobilization, so complementary explorations were finally performed. X-rays revealed a permeative pattern with cortical destruction and soft-tissue involvement, located in the first diaphysis of the right metatarsal (Fig. 1, middle panel). The biopsy and the cytokeratin staining (CK 7–, CK 20+) was compatible with a metastasis of a colorectal adenocarcinoma. The patient received palliative radiotherapy and chemotherapy with oxaliplatin and capecitabine, with an initial partial response, but with bone progression after the eighth course. This time, the location of the progression was the left hemimandibula, intriguingly close to the site of the previous jaw wiring surgery (Fig. 1, left panel). Histology confirmed a metastasis of colorectal adenocarcinoma. Second line chemotherapy with irinotecan was restored, but the patient died of progressive disease in a short time. An autopsy was not performed.
Although early reports described the uncommon finding of metastasis to the site of recent trauma (2), the complex interactions between acute inflammation and micrometastasis progression remained unexplained at that point. Therefore, the gradualistic approach remained safe in the mind of most medical oncologists and scientists.
In 1980s, Walter Alvarez identified the extraterrestrial origin of the cretaceous-tertiary boundary, and dramatically proved that nature and evolution did made leaps. The modern paradigm of evolution has synthesized both opposed elements.
A catastrophic change in the microenvironment due to an external and unpredictable event, such as an accident, appeared to lead to the scenario of tumor arousal. Thus, the report exemplifies and defends a non-progressive view of tumorogenesis. In the field of the evolution of living beings, Stephen Jay Gould called this model the punctuated equilibrium. Applied to the field of tumorogenesis, it implies that metastatic tumor cells change very little during the natural history of disease, but occasionally this tranquility is punctuated by rapid processes of transformation leading to heterogeneity.
At present, it is considered that neoplasms pass through periods of inactivity preceding the phases of growth. This idea has been supported by some animal models of tumorogenesis. Some biphasic patterns of relapse can only be explained on the basis of a dormant phase. The justification of quiescence is not well understood but it probably involves complex interactions between the micrometastatic foci and the host tissues. Animal models have recently proved that early micrometastasis consist of small deposits with no more than 30 tumor cells, most of then arrested in the G0 phase of cell cycle. Subsequently, the avascular colonies dispose forming sleeves around pre-existing vessels. This phase is characterized by a high mitotic index compensated by a high apoptotic rate, so final growth is null (3). The resection of the primary tumor is one of the factors that may alter the kinetics of micrometastasis (4). One of the invoked explanations is the angiogenic switch after the resection, leading to a reduction in the apoptosis rate (5). Other possibility is the acquisition of an angiogenic phenotype by the metastatic cells through stochastic mechanisms. The pattern of tumor relapse in some series seems to behave on this basis (6).
Therefore, the plausible scenario presented in this paper and probably valid in other similar cases describes quiescent micrometastasis diffusely present before the primary tumor was resected. In fact, around 30% of the patients lodge bone marrow micrometastasis at tumor presentation, although only 50% of them progress to clinical disease (7). The hypothesis by Kaplan et al. (8) also points out that before dissemination occurs, hematopoietic precursors with angiogenic phenotype migrate to the premetastatic niches. After that, metastatic stem cells with a clear clonogenic potential reach the bone (9). The influence of the stem cell niches appears to play a critical role in determining the destiny of the micrometastasis (10).
One of the suggestions is that in the adjuvant setting, punctuated equilibrium may imply a strong conceptual frame, and it could be explored in further research. We cannot prevent our patients from unpredictable events, but the underlying issue is whether the molecular network triggered by inflammation and other punctuated phenomena is an effective target to prevent relapses. Although highly debatable, in the future, the aim of specific interventions would have to maintain metastatic cells asleep throughout tissular cataclysms.
Conflict of interest statement
None declared.
References
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