What you sow, the cancer shallth reap.

As a continuum to my previous post, I shall discuss more about the mystery, albeit a fatal one of metastasis. Did you know that most patients succumb to these secondary tumor growths and not necessarily to the primary tumor?

Think of metastasis as branching out of a company from one city to another (refer my previous post for more details). For a Palo Alto-based company, let’s say “Chiquita Bananas :)” to branch out to Los Angeles, may not be an arduous task since they are easily accessible to each other and the city-based logistics are not drastically different. Similarly, metastasis of a breast tumor from one region of the breast to another is also relatively an uncomplicated process. But the common places of breast cancer metastasis are lung, liver and bone; compare this to Chiquita Bananas embarking to Mumbai, a city in India. This would be a challenging task since the language, culture and sensibilities of the two natives are so diverse; in addition to geographical constraints like weather, water and land availability etc. Likewise, in their defined environmental niches tumor cells have learnt to bypass the local hostility at primary tumor site, by both its inherent and acquired manipulation of neighboring environment. However, to migrate from primary site to colonize and grow at specific distant sites, tumor cells have to re-incur hostility in these ‘foreign’ environments. Just as a ‘seed’ requires the right type of ‘soil’ to grow, tumor cells require a suitable environment in the distal organ to metastasize.

To successfully venture to Mumbai, Chiquita Bananas would ‘optimize’ the region overseas, before physical construction begins. For sustainable business, the company would choose a site that has ample water supply, electricity and easy access to transportation. In addition, it would also take into account the type of market it would cater to and its local competition. It is a reasonable strategy for the company to ‘outsource’ to a competent third party to setup the infrastructure overseas rather than take the task upon them. In the same manner, even before tumor cells invade distal organs, they create a permissive environment at the metastatic site indirectly, while present at the primary site. This ‘pre-metastatic niche’ is conditioned either by substances travelling from the primary site or by drafting distinct non-tumor cells to the nascent metastatic site. Tumor cells have been shown to mobilize a specific cell type, called myeloid cells, from bone marrow, a.k.a., the Department of Defense headquarters of our body. Normally these myeloid cells develop into a set of immune cells that heal wounds. These cells remodel the area around an injury, say, a nick on your finger to heal it. Tumor cells release substances that specifically attract these myeloid precursors to the metastatic site. Myeloid precursors are sort of the ‘third party’ equivalent that our company Chiquita’s would outsource to. These cells remodel the metastatic site and make the ‘soil’ there compatible for the ‘seed’, a.k.a., tumor cells. Yes, tumors are wounds that do not heal.

For a more visual perspective of the soil and seed hypothesis of metastasis, consider Pac-man, a popular video game wherein Pac-man has to successfully find its way out of a maze. During its course, it dodges ‘ghosts’ and eats ‘energy pellets’ to gain power. Now imagine Pac-man to be tumor cells and myeloid cell precursors in bone marrow, ghosts. In case of a benign tumor, Pac-man does not have enough energy to venture into the maze and also the myeloid ghosts eat up any stray Pac-man in the maze. Metastasis is a rigged version of the Pac-man game itself! The ghosts that would earlier attack Pac-man now pave the path for them. Pac-man would make its own ‘energy bar’ to help it sustain during its journey through the maze of blood circulation as well as its end point – the metastatic site. It would also make myeloid attracting molecules that would recruit the myeloid cells to metastatic site and remodel the environment there making it tumor-friendly. It is a win-win situation for tumor cells!

Trivia time! The rather radical soil and seed theory of metastasis, a hot field of research today, was actually proposed by an English surgeon Stephen Paget 125 years ago. This reminds me of what Albert Einstein rightly said ‘if at first, the idea is not absurd, then there is no hope for it’.