Can tumors undergo rehab?

So far I have discussed tumors at an organ level. Now let’s zoom-in one magnitude and understand tumors at a cellular level. Tumor is essentially an assortment of rapidly growing cells with diverse flavors of abnormality. Just like a normal cell, tumor cell also needs to carry out its ‘everyday business’ of maintaining its livelihood.

A normal cell has an elaborate yet efficient bureaucracy – depending on the context, recipes for specific proteins are decoded from the DNA into a decipherable RNA. Follow the directions contained in the RNA and voila you get a tailor-made protein! Depending on their function, proteins are then shipped to different areas of the cell; say to mitochondria – the energy house of the cell or to nucleus – the Washington D.C of the cell. Once proteins are at their assigned geographical locations, they relay external information through a defined grid that finally determines the fate of a cell – growth, stasis, aging or death. Notably, there are ‘ying’ proteins that negatively influence and ‘yang’ proteins that positively influence a cellular process. It’s the ratio of the ‘ying’ and ‘yang’ circuitry that finally determines the fate of a cell.

To accommodate for their exceptional rate of growth, an evolving cancer cell harbors several mutations in its genome and hence encoding abnormal proteins. One or more of these mutations may prove to be advantageous to the cancer cell in maintaining its ‘yang’ wiring. As a result tumor cells may become highly dependent or ‘addicted’ to one or more proteins. This phenomenon is called oncogene addiction. Since the abnormal protein(s) is the Achilles heel of tumor, then it is reasonable that removing it would at least impede, if not totally get rid of the disease. In fact, there is clinical evidence for it. For example, Glevec , a drug marketed by Novartis, targets a specific enzyme that a type of white blood cancer, called CML (Chronic Myeloid Leukemia) are addicted to. 95% of CML patients treated with Glevec had a disease free survival for five years – a remarkable achievement in cancer therapeutics.

Studies in mice have shown that different tumors undergoing the ‘de-addiction program’, via forced removal of the abnormal protein (say, protein A), react differently. Some tumors die, some just hang out without growing any further and some age. But as the theory of evolution suggests, a rare population of the original tumor that was insensitive to de-addiction, eventually repopulate – a case of tumor within tumor! This ‘new’ tumor is not addicted to protein A, but may now be heavily dependent on protein B. So theoretically it would respond to protein B de-addiction regime. So the bad news is that there may not be one wonder drug that can cure the tumor completely. But the good news is that a cocktail of drugs may be more effective at keeping aggressive tumor growth at bay…and I believe that we are on the right path to find the right mix :)

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’.