Wednesday, November 04, 2009

Slums in big cities and tumor invasion

In this assay we compare two phenomena: tumorigenesis and the development of slums in big cities, and propose that not only the rules that control their existence are similar but also that the strategies in order to eradicate them are equivalent and that the lessons learned from one problem can be used in the other.

Slums are a grave problem in big cities in underdeveloped and in development countries. In 2007 in São Paulo, the biggest city in Brazil, there were approximately 2,000 slums with a total population of more than 400,000 families living in sub-human conditions. Besides the social problem of this population deprived of minimum sanitary conditions, slums are also safe haven for organized crime and drug dealers and gradually grow by engulfing neighborhoods of the city whose real-state is downgraded by the proximity with them.

Tumors are believed to be created by the relentless replication of genetically unstable cells that, through mutations and selection from microenvironment, acquire a set of phenotypes that allow them to invade healthy tissue, promote angiogenesis and colonize new regions of the host and create new tumors [1, 2], eventually reaching a state of tumor burden that is fatal to the host.

Both phenomena, slums and tumors, often develop in the periphery of the host (carcinomas develop from epithelial tissue separated by host by basement membrane while slums have their origin in the outskirts of towns where real state is less expensive) where resources are limited and uncontrolled growth lead to gradients of resources and harsh conditions.

Both systems invade by “trashing” their surroundings: tumors invade healthy tissue by both degradation of extracellular matrix and by causing death of healthy cells; it is known that tumors constitutively metabolize glucose anaerobically producing lactic acid [3, 4] even in presence of oxygen. It was proposed that this glycolytic phenotype would be a mechanism through which tumors would intoxicate their surroundings in order to kill healthy tissue and make room for new tumor cells [4]. A similar mechanism is found in the periphery of growing slums: a wave of devaluation of real state moves outwards of the slum propagated by criminality which imposes a “bad reputation” to the neighborhood, scaring the dwellers away and leaving room for new residents from the slum periphery or from outside of the system.

Solid tumors are often avascular during the early steps of tumorigenesis and are only able to promote angiogenesis as they achieve a critical mass. The fragile infrastructure of slums is no different from solid tumors: as one progresses into the settlement, the roads become narrower until cars cannot traffic, what considerably reduces efficiency of law enforcement. This inability of law enforcement and a minimum infrastructure for the survival of the slums is similar to what happens in solid tumors. In one side poor perfusion prevents a faster growth of tumor but on the other hand it protects the tumor by preventing the action of the immune system, chemotherapy and radiotherapy by limiting diffusion of drug, inducing quiescence in hypoxic tumor cells and by generating a heterogeneous microenvironment that confers robustness to attack [5].

We have discussed some aspects in how carcinomas and slums develop in a similar manner, notably by uncontrolled population growth in an area in the edge of the host/city with poor infrastructure but also with small or no interference from immune system/law enforcement, as is the case with carcinomas which are separate from immune system by a basement membrane.

Both systems appear to be robust to brute force attacks (toxins and antibiotics in cancer, and law enforcement and eviction in slums) not only because these approaches cause higher side effects in the “host” than in the target but also because the forces that promoted the initial development of these systems remain unchanged (genetic instability and microenvironment-imposed selection for cancer, and social inequality in slums) and thus will promote regrowth of the original system or other similar ones in other areas.

We propose that the most promising strategies for eradicating and preventing carcinomas and slums are those that target the forces that promote their emergence. For carcinomas these strategies would focus on intratumoral pH normalization, use of glucose competitors, use minimum amounts of therapy necessary to arrest tumor growth and delay patient relapse, and finally assess tumor response to therapy in a closed-loop approach. For slums, whose emergence is due to a considerable mass of poor people, the most promising approach would be to invest resources into bringing this share of the society into more equal conditions, which can be achieved by full-time public education with meals and recreational activities in order to keep the children away from one environment permeated by violence, drugs and poverty. Work laws that ensure minimum wages and social programs to provide credit to families to finance homes are also more immediate actions. Finally, the problem of slums in big cities will never be solved if the flow of migrants from poorer underdeveloped regions of the country remains. It is important thus that such an action for reduction of social disparities happens country-wide.

As a final note, we would like to stress that even though slums carry within criminality and major social and public health problems, they only exist and grow because of the initial advantage of cheap labor they offer to the richer population of the cities. An interesting point is that in carcinomas the cells that develop as tumors are exactly those that are isolated in the periphery of the host and considered as “expendable”.

  1. Goldie JH: Drug resistance in cancer: a perspective. Cancer Metastasis Rev 2001, 20:63-68.
  2. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.
  3. Gatenby RA, Gillies RJ: A microenvironmental model of carcinogenesis. Nat Rev Cancer 2008, 8:56-61.
  4. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ: Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 2006, 66:5216-5223.
  5. Kitano H: Cancer robustness: tumour tactics. Nature 2003, 426:125.