1.29.2008
Tumor Microenvironment in Cancer Progression and Metastasis

SPEAKER: Raghu Kalluri, PhD: HMS, MIT, BIDMC
MODERATOR: Jeffrey Borenstein, PhD: Draper Labs, CIMIT

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SUMMARY:

Around twenty million people worldwide are diagnosed with cancer every year, and eight to nine million die.  Cancer is much more prevalent, however, than even these numbers suggest.  Many people have cancerous lesions in their bodies but do not become ill and do not seek medical attention.  Based on autopsy studies, for example, it seems that everyone over the age of fifty has small, dormant carcinomas in the thyroid, although less than one percent will present with cancer in the clinic.  Latent carcinomas in the prostate or breast all also commonly observed.   These lesions have many of the features of invasive cancer but do not exhibit invasive behavior.  It seems that the body’s natural defenses, not just the genetic instability of the cancerous cells themselves, determines to what extent a tumor proliferates.     

Genetic defects in cancerous cells are not responsible for all the observed variation in their growth rates.  The host environment also plays a role.  One way in which systemic factors might affect cancer proliferation involves the “angiogenic switch concept.”  Angiogenesis can promote tumor growth, yet to some extent, angiogenesis is controlled by regulators that circulate throughout the entire body.  Different people will have different background levels of angiogenic regulators, so some people’s bodies will naturally lie closer to the tipping point where angiogenesis is turned “on.”  Thus, according to this hypothesis, tumors will be more likely to prompt angiogenesis in some people than in others not because of differences amongst the tumors but because of background differences amongst the people.  In mice with cancer, for example, the presence or absence of certain genes responsible for inhibiting endothelial proliferation significantly affects survival.

Tumors are not entirely composed of cancerous cells, and researchers still do not know whether non-cancerous cells in a tumor have been recruited to help it grow or whether they are there to contain it.  Fibroblasts, in particular, fulfill mysterious functions.  These cells exhibit marked heterogeneity.  Some inhibit metastasis but not proliferation while others have unknown effects.  The immune system also seems to play an important role in holding back the spread of cancerous cells.  These observations suggest that when considering cancer, one should think about the phase during which there is cancer without disease.  In treating patients, perhaps the goal should be to prolong this phase for as long as possible.  For patients with cancer, perhaps therapy should be focused on restoring the body’s natural checks on proliferation and metastasis, in addition to merely obliterating the cancer and hoping it doesn’t come back.